Treatment of congestive heart failure with growth hormone secretagogues

ABSTRACT

The present invention is directed to methods for the modulation of cardiac function which comprise the administration of certain compounds, as defined herein, having growth hormone secretagogue activity.

This is a 371 PCT/US98/17201 Filed Aug. 19, 1998 which claims benefit toU.S. Provisional Application No. 60/056,135 filed Aug. 19, 1997.

Congestive heart failure (CHF; cardiac failure) is a condition in whichweakened heart function exists together with a build-up of body fluid.Cardiac failure often occurs when cardiac output is insufficient to meetmetabolic demands of the body, or when the heart cannot meet the demandsof operating at increased levels of filling/diastolic pressure.

Congestive heart failure may be caused by many forms of heart disease.Common causes of congestive heart failure include: narrowing of thearteries supplying blood to the heart muscle (coronary heart disease);prior heart attack (myocardial infarction) resulting in scar tissuelarge enough to interfere with normal function of the heart; high bloodpressure; heart valve disease due to past rheumatic fever or anabnormality present at birth; primary disease of the heart muscle itself(cardiomyopathy); defects in the heart present at birth (congenitalheart disease) and infection of the heart valves and/or muscle itself(endocarditis and/or myocarditis). Each of these disease processes canlead to congestive heart failure by reducing the strength of the heartmuscle contraction, by limiting the ability of the heart's pumpingchambers to fill with blood due to mechanical problems or impaireddiastolic relaxation, or by filling the heart's chambers with too muchblood.

Numerous compounds are known in the art to be useful for the preventionand treatment of congestive heart failure, including α-adrenergicantagonists, angiotensin II antagonists, angiotensin-converting enzyme(ACE) inhibitors, β-adrenergic antagonists, antihypertensives, calciumchannel blockers, diuretics, potassium channel opening vasodilators,renin inhibitors, and serotonin antagonists.

Growth hormone, which is secreted from the pituitary gland, stimulatesgrowth of all tissues of the body that are capable of growing. Inaddition, growth hormone is known to have the following basic effects onthe metabolic processes of the body: (1) increased rate of proteinsynthesis in all cells of the body; (2) decreased rate of carbohydrateutilization in cells of the body; and (3) increased mobilization of freefatty acids and use of fatty acids for energy. The cardiac effects ofgrowth hormone have been reviewed, and it is suggested that growthhormone plays a role in the modulation of cardiac performance and themaintenance of normal cardiac structure and performance. The effects ofgrowth hormone on heart function is discussed in Sacca, et al.,Endocrine Rev. 15: 555-573, 1994. Further, dramatic effects of growthhormone on heart failure have been observed clinically (Fazio et al.,New England Journal of Medicine, 334: 809-14, 1996).

A deficiency in growth hormone secretion can result in various medicaldisorders, depending on the age of onset. In children, the syndrome ischaracterized by short stature, with normal body proportions and reducedgrowth rate, also known as dwarfism. A deficiency in growth hormonesecretion later in life may be characterized by excessive adiposity,reduced muscle mass, impaired exercise capacity, reduced body water,decreased bone mineral density, and psychological disorders. Forexample, a deficiency in growth hormone may result in myocardialdysfunction, in particular left ventricular diastolic dysfunction.Shahj, et al., Br. Heart J., 67, 92-96 (1992). A deficiency in growthhormone also has been suggested to be a factor in increased mortalityfrom cardiovascular disease of adults with growth-hormone deficiency.Rosen, Lancet, 336, 285-288 (1990).

Supplemental growth hormone administered for a four month period togrowth hormone-deficient adults was reported to have no significanteffect on left ventricular mass. Jorgenson, et al., Lancet, 1221-1225(1989); Shajh, et al., Br. Heart J., 67, 92-96 (1992). However, whenadministered to growth-hormone deficient adults over a six month period,supplemental growth hormone increased left ventricular mass, andprovided favorable cardiovascular effects including increased cardiacoutput and glomerular filtration rate and reduced peripheral vascularresistance. Caldahl, et al., Clinical Endocrinology, 40, 393-400 (1994).In a patient suffering from growth hormone deficiency and poor cardiacfunction, supplemental growth hormone resulted in improvement inmyocardial contractility and cardiac output. Cuneo et al., Lancet, 1,838-839 (1989). Supplemental growth hormone therapy in growth hormonedeficient adults was found to improve resting and exercise cardiacfunction, but at the expense of ventricular hypertrophy. Fort, et al.,Circulation, 90, (4, Part 2) pg. I-610, abs. 3290 (1994). However, theeffects of growth hormone in human heart failure patients without growthhormone deficiency have not been reported.

Certain compounds have been developed which stimulate the release ofendogenous growth hormone. These compounds are also called growthhormone secretagogues. Growth hormone releasing peptides GHRP-6 andGHRP-1 (GRP-1 and GRP-6) are described in U.S. Pat. No. 4,411,890 andPCT Patent Publications WO 89/07110 and WO 89/07111. Growth hormonereleasing peptide GHRP-2 (GRP-2) is described in PCT Patent PublicationWO 93/04081, and hexarelin is described in J. Endocrinol. Invest., 15(Suppl 4), 45 (1992). Growth hormone releasing peptides (GHRPs) are alsodescribed in Bowers et al., Endocrinology 114: 1537-45 1984. Inaddition, small organic molecules having growth hormone secretagogueactivity have also been described in Jacks et al., Endocrinology 137:5284-9, 1996.

Other compounds with growth hormone secretagogue activity are discussedin U.S. Pat. Nos. 3,239,345; 4,036,979; 4,411,890; 5,206,235; 5,248,841;5,310,737; 5,310,017; European Patent Publication 144,230; EuropeanPatent Publication 513,974; Patent Cooperation Treaty Patent PublicationWO 94/07486; Patent Cooperation Treaty Patent Publication WO 94/08583;Patent Cooperation Treaty Patent Publication WO 94/13696; Science,260:1640-1643 (1993), Ann. Rep. Med. Chem., 28, 177-186 (1993); Bioorg.Med. Chem. Ltrs., 4 (22), 2709-2714 (1994); PNAS 92, 7001-7005 (July1995); British Patent Application GB 2308064A, U.S. Ser. No. 08/704,494,filed Aug. 20, 1996, and U.S. Ser. No. 08/700,206, filed Aug. 20, 1996.Additional compounds with growth hormone secretagogue activity aredescribed herein.

Recent advances in heart failure therapy have demonstrated it ispossible not only to alter the progression of heart failure, but also,in the case of antiadrenergic therapy with β-blockers, to partiallyreverse systolic dysfunction and ventricular remodeling of the failedmyocardium (Eichhorn and Bristow, Circulation 94: 2285-96, 1996. In thecase of Carvedilol®, these effects upon heart failure appear to resultin dramatic reductions in mortality in patients (Packer et al., NewEngland Journal of Medicine 334: 1349-55, 1996). Improved biologicalfunction of the cardiomyocyte appears to play an important role in thebeneficial effects of β-blockade in experimental heart failure (Tsutsuiet al., J. Clin. Invest. 93: 2639-2648, 1994). These observationsindicate the reversible nature of congestive heart failure.

Although β-blockers and ACE inhibitors represent significantcornerstones for the treatment of heart failure, important medicalissues remain concerning quality of life and survival. Thus, noveltherapeutic approaches to congestive heart failure that improve survivalrate as well as the indices of quality of life, and that are alsoconvenient for both patient and physician remain an important unmetmedical need.

Thus, it would be a significant contribution to the art to providecompounds and methods of using same that promote the secretion of growthhormone for use in the prevention, inhibition, or treatment ofcongestive heart failure as indicated herein.

The instant invention relates to methods for the modulation of cardiacfunction which comprise the administration of a compound having growthhormone secretagogue activity.

The present invention yet further relates to methods for the treatmentor prevention of congestive heart failure, which method comprisesadministering to an animal in need of said treatment an effective amountof a compound having growth hormone secretagogue activity.

The present invention still further relates to methods for the treatmentor prevention of congestive heart failure, which method comprisesadministering to an animal in need of said treatment an effective amountof GRP-2.

The present invention still further relates to methods for the treatmentor prevention of congestive heart failure, which method comprisesadministering to an animal in need of said treatment an effective amountof a compound of formula I having growth hormone secretagogue activity,wherein a compound of formula I is represented by

wherein:

A is C₁-C₆alkyl, aryl, C₁-C₆alkylaryl, C₁-C₆alkyl(O)C₁-C₆alkylaryl,C₁-C₆alkyl(S)C₁-C₆alkylaryl, indolyl, indolinyl, thienyl,(C₁-C₆alkyl)thienyl, benzothienyl, benzofuranyl, naphthanyl, cyclohexyl,(C₁-C₆alkyl)indolyl, (C₁-C₆alkyl)benzothienyl, (C₁-C₆alkyl)naphthanyl,(C₁-C₆alkyl)benzofuranyl, and (C₁-C₆alkyl)cyclohexyl;

B is NH₂, NHR₁, C₁-C₆alkylNH₂, C₁-C₆alkylNHR₁, C₁-C₆alkylarylNH₂,C₁-C₆alkylarylNHR₁, C₁-C₆alkylcyclohexylNH₂, C₁-C₆alkylcyclohexylNHR₁,R₁-piperidin-3-yl(C₁-C₆alkyl), R₁-piperidin-2-yl(C₁-C₆alkyl),R₁-piperidin-4-yl(C₁-C₆alkyl), R₁-quinolin-2-yl(C₁-C₆alkyl),R₁-(2,4-dihydroquinolin-2-yl(C₁-C₆alkyl),R₁-isoquinolin-2-yl(C₁-C₆alkyl), and R₁-(2,4-dihydroisoquinolin-2-yl(C₁-C₆alkyl);

R₁ is hydrogen, C₁-C₆alkyl, C₁-C₆alkyl(OH), or C₁-C₆alkylidenyl (OH)R₂;

R₂ is C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkyl(O)C₁-C₆ alkyl, C(O)O—C₁-C₆alkyl, aryl, or C₁-C₆alkylaryl;

X is C₁-C₆alkylidenyl, O, S, NH, or N(C₁-C₆alkyl);

V is selected from the group consisting of

W is S, O, NH, or CH₂;

Y is N or CH;

Z is N or CH;

Y′ is N or CH;

Z′ is N or CH;

R₄ and R₅ are independently hydrogen, C₁-C₆alkyl, aryl, C₁-C₆alkylaryl,C(O)O(C₁-C₆alkyl), C(O)N(C₁-C₆alkyl)₂, or C₁-C₆alkylCOR₇;

R₇ is hydrogen, C₁-C₆alkyl, pyrrolidinyl, piperidinyl, homoproline, orproline;

D is hydrogen, C₁-C₆alkyl, C₁-C₆alkyl(O)(CO)C₁-C₆alkyl,C₁-C₆alkyl(O)(CO)N(C_(C) ₆alkyl)₂, C₁-C₆alkylaryl, C(O)R₆,C₁-C₆alkyl(O)R₆, C₁-C₆alkyl(OH), C₁-C₆ alkylC(O)R₆, C₁-C₆alkylR₆, aryl,(C₁-C₆alkyl)NHSO₂(C₁-C₆alkyl), (C₁-C₆alkyl)NHSO₂(aryl);

R₆ is H, C₁-C₆alkyl, aryl, naphthyl, C₁-C₆alkylaryl, acetyl, NH₂,NH(C₁-C₆alkyl), NH(C₁-C₆alkyl)O(C₁-C₆alkyl),NH(C₁-C₆alkyl)S(C₁-C₆alkyl), NH(C₁-C₆alkylidenyl)OCH₃,NH(C₁-C₆alkyl)aryl, NH(C₃-C₆ cycloalkyl),NH(C₁-C₆alkyl)C(O)(C₁-C₆alkyl), NH(C₁-C₆alkyl)NH(C₁-C₆alkyl),NH(C₁-C₆alkyl)NH(C₁-C₆alkylaryl), NHSO₂(C₁-C₆alkylaryl),NH(C₁-C₆alkyl)C(O)O(C₁-C₆alkyl), NH(naphthyl), N(C₁-C₆alkyl)2,N(C₁-C₆alkyl)(aryl), N(C₁-C₆alkyl)(C₁-C₆alkylaryl), O(C₁-C₆alkyl),O(aryl), O(C₁-C₆alkylaryl), piperidinyl, piperidinyl-C(O)NH(C₁-C₆alkyl),piperidinyl-C(O)NH(C₁-C₆alkylaryl), piperidinyl-C(O)N(C₁-C₆alkyl)₂,piperidinyl-C(O)N(C₁-C₆alkyl)(aryl), pyrrolidinyl, pyrrolidinylC(O)NH(aryl)-, pyrrolidinyl C(O)NH(C₁-C₆alkyl)-, pyrrolidinylC(O)NH(C₁-C₆alkylaryl)-, pyrrolidinyl C(O)N(C₁-C₆alkyl)₂-, pyrrolidinylC(O)N(C₁-C₆alkyl)(aryl)-, pyrrolinyl, morpholino, hexamethyleneimino,heptamethyleneimino, quinolinyl, 2,4-dihydroquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,4-dihydroisoquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, indolinyl, an amino acid selected fromthe group consisting of proline, homoproline, glycine, alanine, valine,leucine, isoleucine, tyrosine, tryptophan, phenylalanine, serine,threonine, asparagine, glutamic acid, aspartic acid, lysine, arginine,glutamine, histidine, cysteine, and methionine, or a nitrogen-containingheterocycle selected from the group consisting of

E is hydrogen, C₁-C₆alkyl, C(O)C₁-C₆alkyl, aryl, (aryl)C(O)NR₆,(aryl)(C₁-C₆alkyl)C(O)R₆, C₁-C₆alkylaryl, C(O)aryl, C₁-C₆alkylC(O)aryl,naphthyl, C₁-C₆alkylnaphthyl, C(O)naphthyl, C₁-C₆alkylC(O)naphthyl,heteroaryl, C₁-C₆alkylheteroaryl, C(O)heteroaryl, C₁-C₆alkylC(O)heteroaryl, indanyl, C₁-C₆alkylindanyl, C(O)indanyl,C₁-C₆alkylC(O)indanyl, cycloalkyl;

or D and E combine to form indanyl, fluorenyl, or cycloalkyl;

G is hydrogen, C₁-C₆alkyl, aryl, C₁-C₆alkylaryl, and C₁-C₆alkenyl;

J is hydrogen, C₁-C₆alkyl, aryl, and C₁-C₆alkylaryl;

L is hydrogen, C₁-C₆alkyl, C(O)OC₁-C₆alkyl, aryl, C₁-C₆alkylaryl,C(O)OC₁-C₆alkylaryl, C₁-C₆alkenyl, —F, and —CN, C₁-C₆alkyl-OH,C₁-C₆alkyl-O—C₁-C₆alkyl, C₁-C₆alkyl-C(O)R₆;

or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to pharmaceutical formulationscontaining a growth hormone secretagogue alone or in combination withadditional therapeutic agents useful for the treatment or prevention ofcongestive heart failure.

Also provided are pharmaceutical formulations of GRP-2 alone or incombination with additional therapeutic agents useful for the treatmentor prevention of congestive heart failure.

Further provided are pharmaceutical formulations of a compound offormula I alone or in combination with additional therapeutic agentsuseful for the treatment or prevention of congestive heart failure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B and 1C illustrates the differences in heart and lung weightobserved between the administration of growth hormone and GRP-2 in theSHHF rat model of CHF.

FIG. 2 illustrates pre-dosing levels of corticosterone in rats.

FIG. 3 illustrates levels of corticosterone in rats treated with growthhormone or GRP-2 after one month.

FIG. 4 illustrates levels of corticosterone in rats treated with growthhormone or GRP-2 at the end of the study.

FIG. 5 illustrates pre-dosing levels of atrial natriuretic peptide (ANP)in rats.

FIG. 6 illustrates levels of atrial natriuretic peptide (ANP) in ratstreated with growth hormone or GRP-2 after one month.

FIG. 7 illustrates levels of atrial natriuretic peptide (ANP) in ratstreated with growth hormone or GRP-2 at the end of the study.

FIG. 8 illustrates end systolic volume in rats treated with growthhormone or CRP-2.

(Note: Data presented in FIGS. 1-7 is +/−standard error of means. Datapresented in FIG. 8 is +/−standard deviation.)

The term “growth hormone secretagogue” means any exogenouslyadministered compound that directly or indirectly stimulates orincreases the endogenous release of growth hormone in an animal. Thegrowth hormone secretagogue may be peptidyl or nonpeptidyl in nature.

The growth hormone secretagogue may be used alone or in combination withother growth hormone secretagogues, or with other therapeutic agentsknown to be beneficial in the treatment of hypertension or the treatmentor prevention of congestive heart failure, at least as discussed supra.Administration of same may be concomitant or sequential.

Improving overall pulmonary function in a patient suffering fromcongestive heart failure is also included in the scope of the presentinvention. In addition, the administration of a growth hormonesecretagogue is also useful for diminishing or preventing loss of bodyweight and enhancing recovery following congestive heart failure.

Administration of a growth hormone secretagogue more closely mimicsbiological functionality than the administration of growth hormonesubcutaneously. For example, bolus or acute administration of GHRPsleads to an acute, transient release of growth hormone from pituitarystores, but the chronic administration of same results in an enhanced,pulsatile release of growth hormone. The latter therapeutic approachmore closely mimics the natural, physiological release of endogenousgrowth hormone. The terms and abbreviations used in the instant exampleshave their normal meanings unless otherwise designated. For example “°C.” refers to degrees Celsius; “N” refers to normal or normality; “mmol”refers to millimole or millimoles; “g” refers to gram or grams; “ml”means milliliter or milliliters; “M” refers to molar or molarity; “MS”refers to mass spectrometry; “FDMS” refers to field desorption massspectrometry; “UV” refers to ultraviolet spectroscopy; “IR” refers toinfrared spectroscopy; and “NMR” refers to nuclear magnetic resonancespectroscopy.

As used herein, the term “C₁-C₆ alkyl” refers to straight or branched,monovalent, saturated aliphatic chains of 1 to 6 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term “C₁-C₆alkyl” includes within its definition the term “C₁-C₄ alkyl”.

As used herein, the term “cycloalkyl” refers to cyclized chains of 1 to6 carbon atoms and includes, but is not limited to, cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Halo” represents chloro, fluoro, bromo or iodo.

“C₁-C₆ alkoxy” represents a straight or branched alkyl chain having fromone to six carbon atoms attached to an oxygen atom. Typical C₁-C₆ alkoxygroups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and the like. The term “C₁-C₆ alkoxy” includes within itsdefinition the term “C₁-C₄ alkoxy”.

“C₂-C₆ alkanoyl” represents a straight or branched alkyl chain havingfrom one to five carbon atoms attached through a carbonyl moiety.Typical C₂-C₆ alkanoyl groups include ethanoyl (also referred to asacetyl), propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl,hexanoyl, and the like.

“C₁-C₆ alkylidenyl” refers to a straight or branched, divalent,saturated aliphatic chain of one to six carbon atoms and includes, butis not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl,butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl,hexylenyl, and the like.

The term “aryl” represents an aromatic ring or rings including phenyl,napthyl, biphenyl, and aromatic residues of 5 to 7-membered rings with 1to 4 heteroatoms (a “heteroaryl”), all of which may be optionallysubstituted with one or more substituents, including C₁-C₆ alkyl,—OC₁-C₆ alkyl, —OCF₃, amide, NHamide, carboxamide, sulfonamide,NHsulfonamide, imide, hydroxy, carboxy, nitro, chloro, fluoro,tri(chloro or fluoro)methyl, cyano, and the like. The aromatic ring maybe attached at any carbon atom or heteroatom which affords a stablestructure. 3,4-methylenedioxyphenyl is included here.

The term “heterocycle” represents a stable 5- to 7-membered monocyclicor 7- to 10-membered bicyclic heterocyclic ring which is saturated orunsaturated and which consists of carbon atoms and from 1 to 4heteroatoms selected from the group consisting of nitrogen, oxygen orsulfur, and wherein the nitrogen and sulfur heteroatoms may optionallybe oxidized, and the nitrogen heteroatom may optionally be quaternizedand including a bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached at any heteroatom or carbon atom which affords a stablestructure, and may be optionally substituted with one or moresubstituents selected from the group consisting of C₁-C₆ alkyl, —OC₁-C₆alkyl, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl,and the like.

The term “carboxy-protecting group” as used herein refers tosubstituents of the carboxy group commonly employed to block or protectthe carboxy functionality while reacting other functional groups on thecompound. Examples of such protecting groups include methyl, ethyl,p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl,pentamethylbenzyl, 3,4-methylene-dioxybenzyl, benzhydryl,4,4′-dimethoxybenzhydryl, 2,2′,4,4′-tetramethoxybenzhydryl, t-butyl,t-amyl, trityl, 4-methoxytrityl, 4,4′-dimethoxytrityl,4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl,t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and the like. A preferredcarboxy-protecting group for the practice of the present invention ismethyl or ethyl. Further examples of these groups may be found in E.Haslam, supra, at Chapter 5, and T. W. Greene, et al., supra, at Chapter5.

The term “amino-protecting group” as used herein refers to substituentsof the amino group commonly employed to block or protect the aminofunctionality while reacting other functional groups on the compound.Examples of such amino-protecting groups include formyl, trityl,phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, andurethane-type blocking groups such as benzyloxycarbonyl,4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-chlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, n-butoxycarbonyl,(NBoc)t-butoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxy-carbonyl (FMOC),2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,isobornyloxycarbonyl, 1-piperidyloxycarbonyl, and the like;benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphineoxide and like amino-protecting groups.

The amino-protecting group employed is usually not critical so long asthe derivatized amino group is stable to the condition of subsequentreactions on other positions of the intermediate molecule, and may beselectively removed at the appropriate point without disrupting theremainder of the molecule including any other amino-protecting groups. Apreferred amino-protecting group for the practice of the presentinvention is t-butoxycarbonyl (NBoc). Further examples of groupsreferred to by the above terms are described by E. Haslam, ProtectiveGroups in Organic Chemistry, (J. G. W. McOmie, ed., 1973), at Chapter 2;and T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis (1991), at Chapter 7.

The term “leaving group” (Q) refers to a group of atoms that isdisplaced from a carbon atom by the attack of a nucleophile in anucleophilic substitution reaction. Suitable leaving groups includebromo, chloro, and iodo, benzenesulfonyloxy, methanesulfonyloxy, andtoluenesulfonyloxy. The term “leaving group” (Q) includes activatinggroups.

The term “activating group” as used herein refers a leaving group which,when taken with the carbonyl (—C═O) group to which it is attached, ismore likely to take part in an acylation reaction than would be the caseif the group were not present, as in the free acid. Such activatinggroups are well-known to those skilled in the art and may be, forexample, succinimidoxy, phthalimidoxy, benzotriazolyloxy, azido, or—O—CO—(C₄-C₇ alkyl).

The compounds used in the method of the present invention may have oneor more asymmetric centers. As a consequence of these chiral centers,the compounds of the present invention occur as racemates, mixtures ofenantiomers and as individual enantiomers, as well as diastereomers andmixtures of diastereomers. All asymmetric forms, individual isomers andcombinations thereof, are within the scope of the present invention.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in Nomenclature of Organic Compounds:Principles and Practice, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

In addition to the (R)-(S) system, the older D-L system is also used inthis document to denote absolute configuration, especially withreference to amino acids. In this system, a Fischer projection formulais oriented so that the number 1 carbon of the main chain is at the top.The prefix “D” is used to represent the absolute configuration of theisomer in which the functional (determining) group is on the right sideof the carbon atom at the chiral center and “L”, that of the isomer inwhich it is on the left.

In order to preferentially prepare one optical isomer over itsenantiomer, a number of routes are available. As an example, a mixtureof enantiomers may be prepared, and then the two enantiomers may beseparated. A commonly employed method for the resolution of the racemicmixture (or mixture of enantiomers) into the individual enantiomers isto first convert the enantiomers to diastereomers by way of forming asalt with an optically active acid or base. These diastereomers may thenbe separated using differential solubility, fractional crystallization,chromatography, or the like. Further details regarding resolution ofenantiomeric mixtures may be found in J. Jacques, et al., Enantiomers,Racemates, and Resolutions, (1991).

Preferred compounds of the present invention are compounds of formula Iwherein:

A is

B is

J is H;

G is H;

X is NH;

V is

E is

D is —C(O)R₆, where R₆ is 1-pyrrolidinyl, 1-piperidinyl,4-methyl-1-piperidinyl, N,N-dimethyl,

L is H or CH₃;

or a pharmaceutically acceptable salt or solvate thereof.

A preferred compound includes a compound of formula Id provided below:

Also preferred are compounds of formula IA and IB provided hereinabove.

During any of the following synthetic sequences it may be necessary ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by employing conventionalprotecting groups as described, supra.

The compounds of the present invention may be prepared by a number ofroutes, many of which are known to those of skill in the art. Theparticular order of steps to be employed in the synthesis of compoundsof formula I is dependent upon the compound to be synthesized, thestarting material employed, and the relative lability of the varioussubstituted moieties. Examples of such synthetic routes may be found inSchemes I through IV provided below, as well as in the Examples.

One synthetic route to compounds of the present invention is provided inScheme I below. The compounds of formula IV′ and IV are commerciallyavailable, or may be prepared using techniques known in the art. Acompound of formula IV may be prepared from a compound of formula IV′through an intermediate acid chloride prepared by standard methods usingthionyl chloride or oxalyl chloride. Treatment of the resulting acidchloride with a bromine source, such as N-bromosuccinimide, followed byquenching of the acid chloride with ethanol, results in compounds offormula IV. It is to be understood that the bromine group on thecompound of formula IV may in fact be any suitable leaving group (Q), asdefined herein. This preparation is provided below in Scheme IA.

wherein R is representative of E as defined in a compound of formula Iabove.

The starting material further includes compounds of formula V, which arecommercially available, or may be routinely synthesized using techniquesreadily known in the art. Compounds of formula IV may be coupled with acompound of formula V (4-nitroimidazole) by methods known in the art togenerate a compound of formula IIb′. Suitable agents to be employed inthe coupling of these compounds include the treatment of a compound offormula IV with an organic or inorganic base, followed by reaction withthe bromo compound of formula IV. Standard organic bases includetrialkylamines, potassium hexamethyldisilazide, lithiumhexamethyldisilazide, lithium diisopropylamide, potassium carbonate, andthe like. Preferred for the practice of the present invention is sodiumhydride or potassium carbonate in dimethylformamide. A compound offormula IIb′ is then deprotected to provide a compound of formula IIb,using lithium hydroxide, although other deprotecting reagents may beemployed in this reaction. Such deprotecting agents include standardsaponification reagents such as sodium hydroxide, potassium hydroxide,and lithium hydroxide.

Substantially pure (R) enantiomers of compounds of formula IIb may alsobe synthesized by methods provided in U.S. Pat. Nos. 5,344,937 and5,380,866, the disclosures of which are herein incorporated byreference.

A compound of formula IIb is then converted to the corresponding amideunder appropriate conditions with a compound of formula VI to generate acompound of formula IIa. In general, amidation of primary or secondaryamines of formula VI may be accomplished by a number of methods known inthe art in which activation of the acid to form a better leaving groupis the initial step. Suitable activating agents for this are also knownin the art and include dicyclohexycarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) withhydroxybenzotriazole (HOBT), oxalyl chloride, thionyl chloride, PyBOP®(benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate),and the like. Preferred for the practice of the present invention ishydroxybenzotriazole (HOBT). The nitro group on the resulting compoundof formula IIa may then be reduced to an amino group using any suitablemeans, employing a suitable reducing agent. Preferred for the practiceof the present invention is a catalytic reduction employing hydrogen and5% palladium on carbon. A compound of formula II is produced by thisreduction reaction.

The preferred reaction temperature range employed in these reactions isbetween −40 and 150° C., and the most preferred range is between 10 and40° C. These reactions may be conveniently carried out in situ, withoutisolation of the particular compound after its preparation.

Examples of these reactions are provided below in Scheme I.

wherein R is representative of E as previously defined, and R₂R₁N is R₆as previously defined.

A second portion of the overall synthesis of compounds of formula I isprovided in Scheme II below. Representative starting material for thissynthesis is a compound of formula IIIb′, which is achemically-protected form of the amino acid O-serine. Bychemically-protected it is meant that both the amino- andcarboxy-functional groups have been suitably protected in order tofacilitate further reactions with this molecule. Such protectionreactions are known to those of skill in the art, and may be applied toother suitable starting materials. Intermediates of formula IIIb′ arecommercially available, or may be prepared by standard syntheses ofamino acids. Such syntheses are well known to persons of ordinary skillin the art and are described, for example, in Chemistry and Biochemistryof Amino Acids, (G. C. Chapman ed., 1985). The protected amino group maybe specifically deprotected using trifluoroacetic acid and methylenechloride to allow for further reactions with this amino functionalgroup. This deprotection reaction results in a compound of formula IIIb.

A compound of formula IIIb may then be N-acylated with anamino-protected compound of formula X to produce a compound of formulaIIIa′. Suitable activating agents for this N-acylation reaction areknown in the art and include DCC, HOBT, EDC, and oxalyl chloride.Preferred for the practice of the present invention is HOBT. Compoundsof formula X are commercially available, or are readily prepared fromsuitable available starting materials. The protected carboxy group onthe compound of formula IIIa′ is then selectively deprotected, typicallyusing lithium hydroxide, to generate a compound of formula III.Compounds of formula III in which the starting material IIIb′ is2-Nboc-amino-pentanoic acid methyl ester may also be prepared by theroute described in Scheme II.

A compound of formula III is then coupled with a compound prepared fromthe reduction of IIb′ with hydrogen and a palladium catalyst employing acoupling reaction to generate a compound of formula Ia. Again, typicalreagents for this N-acylation are known in the art, and include DCC andHOBT, which is the preferred method of coupling employed in the practiceof the present invention. A compound of formula Ia is then selectivelydeprotected at the carboxy group, coupled at this site with a compoundof formula VI, and then further deprotected at the amino group togenerate a compound of formula Ia. Suitable agents for thesedeprotection and coupling reactions are discussed, infra, and are knownin the art. Compounds of formula Ia are encompassed by formula I, andare pharmaceutically active.

The preferred reaction temperature range employed in these reactions isbetween −40 and 150° C., and the most preferred range is between 10 and40° C. These reactions may be conveniently carried out in situ, withoutisolation of the particular compound after its preparation.

Alternatively, compounds of formula IIa can be coupled. with compoundsof formula III to provide intermediates which can be deprotected to givecompounds of formula Ia.

Representative reactions are provided below in Scheme II.

wherein R is E as previously defined, and R₂R₁N is R₆ as previouslydefined.

An alternative synthetic scheme is provided in Scheme III below. Acompound of formula VII (5-nitrobenzimidazole) is commerciallyavailable, or may be conveniently prepared using reactions known in theart. A compound of formula VII is coupled with a compound of formula IVin an alkylation reaction, using coupling agents as discussed, infra. Acompound of formula VIII′ is produced in which the carboxy functionalgroup is protected. This protecting group is then removed as previouslydiscussed, typically using lithium hydroxide, followed by coupling witha compound of formula XII. The nitro group on the resulting compound offormula VIII is then reduced, followed by coupling with a compound offormula III. The resulting compound of formula Ib′ is then deprotectedto provide a compound of formula Ib. Compounds of formula Ib areencompassed by formula I, and are pharmaceutically active. Thesereactions are provided below in Scheme III.

A still further representative synthesis of compounds of formula I isprovided below in Scheme IV. Starting materials of formula IX(3-amino-nitrobenzene) are commercially available. Initially, a compoundof formula IX is coupled with a compound of formula IV by meansdiscussed previously. The resulting compound of formula XI′ is thendeprotected, followed by coupling with a compound of formula XII toprovide a compound of formula XI. A compound of formula XI is thenreduced and further coupled in an N-acylation reaction with a compoundof formula III. The resulting compound of formula Ic′ is thendeprotected to result in a compound of formula Ic. Conditions for thesereactions have been discussed previously. Compounds of formula Ic areencompassed by formula I, and are pharmaceutically active.

In addition to the Schemes described hereinabove, an enantiospecificprotocol for the preparation of the compounds of formula I may beemployed. Typically, a synthetic reaction design which maintains thechiral center present in the starting material in a desired orientationis chosen. The preferred reaction schemes are those that generallyproduce compounds in which greater than 95 percent of the product is thedesired enantiomer. In Scheme V below, R-substituted phenyl isrepresentative of the E substituents as provided in compounds of formulaI above. Further, the -methylene-X moiety is representative of the Asubstituents in compounds of formula I above.

The following discussion is directed to the reactions provided in SchemeV. Specifically, the reactions of compounds of formula I, II, and IIIare as provided in the discussion of Scheme I hereinabove.

A compound of formula IV may be prepared by the alkylation of a compoundof formula III by standard methods using a base, such as sodium hydride,followed by treatment with an electrophile, such as methyl iodide.Preferred bases for this reaction include sodium-, lithium-, orpotassium hexamethyldisilazide, lithium dilsopropylamide, and sodiumhydride. Preferred methylating agents include methyl halides or anymethyl group with a suitable substituted leaving group such as toslyate,mesylate, and the like.

A compound of formula V may be prepared by hydrolysis of a compound offormula IV using standard saponfication conditions known in the art.Suitable reagents for this transformation include sodium hydroxide orlithium hydroxide. The resulting carboxylic acid may be converted intothe acid chloride by standard methods using thionyl chloride or,preferably, oxalyl chloride. The acid chloride may then be reacted withthe lithium salt of a chiral auxiliary, such as(4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone, to provide compounds offormula V and VI, which are readily separable by silica gelchromatography.

A compound of formula VII may be prepared by the removal of the chiralauxiliary under basic conditions, such as lithium hydroxide. Otherreagents known in the art for removing oxazolidinone-type chiralauxiliaries may be used for this transformation. These include lithiumhydroxide/hydroperoxide conditions, reduction/oxidation protocols, alkylsulfur displacements, and transaminations.

A compound of formula VIII may be prepared from a compound of formulaVII by standard methods known in the art. Formation of the acid chlorideusing oxalyl or thionyl chloride followed by reaction with a suitablesubstituted amine (NR₂) provide compounds of formula VIII.

A compound of formula IX may be prepared by the reduction of a compoundof formula VIII using hydrogen with palladium on carbon. Other methodsknown in the art which may be employed for the reduction of the nitrogroup include the use of tin(II)chloride, iron in an acidic solution,ferrous sulfate and aqueous alkali, activated alumina, and sodiumsulfite. The resulting 4-amino imidazole compound of formula VIIa isthen reacted directly with the appropriate dipeptide acid (a compound offormula IIX) under standard peptide coupling conditions involvingformation of the active ester of the dipeptide followed by reaction withamine VIIa. Conditions suitable for amide formation include DCC, EDC,with HOBT. A compound of formula IIX may be prepared from the methylester of unnatural D-amino acids such as D-benzyloxyserine,D-tryptophan, and D-2-amino-5-phenyl-pentanoic acid and the like whichare known in the art. Standard coupling protocols involving formation ofthe active ester of the amino acid using DCC/HOBt followed by reactionwith N-Boc-aminoisobutyric acid provide dipeptide acids of formula IIX.

The Boc protecting group of a compound of formula IX may be removedunder standard acidic conditions such as hydrochloric acid in aceticacid or ethyl acetate, trifluoroacetic acid, tetramethyliodosilane,aluminum chloride, sulfuric acid in dioxane, and methanesulfonic acid.

An additional method of preparing diastereomeric compounds of formula Iinvolves the use of a chromatographic column which employs a chiralphase. An example of such a preparation may be found in Examples Part 6as provided hereinbelow.

Preferred for the practice of the present invention are those compoundsof formula I wherein the indicated stereochemistry is (R,R) at the twochiral centers. An example of this preferred stereochemistry is providedby compounds of formula IA and IB as provided hereinabove.

Two additional Schemes for providing chiral intermediates are providedhereinbelow as Schemes VA and VB. As described in Scheme VA, opticallypure aryl glycine amino acids may be protected at the amino position byreaction with a suitable protecting group, such as Boc. Reaction of theBoc protected intermediate with a standard methylating agent, such asmethyl iodide, may provide the corresponding phenolic methyl ether. Thecarboxamide may be prepared by coupling with an amine, such asdimethylamine, pyrrolidine, or 4-methyl piperidine, using standardcoupling techniques. Preferred coupling agents for the invention arediethy cyanophosphorane (DECP), triethylamine and the amine at 0° C. TheBoc protecting group may be removed under standard acidic conditions,with trifluoroacetic acid being preferred. The desired 4-nitroimidazolecompounds can be prepared by reaction of the free amine with1,4-dinitroimidazole to give optically pure compounds, as determined bychiral HPLC. Such chiral intermediates can be processed as described inSchemes I and II to provide diastereomerically pure products. Forexample, the chiral nitroimidazoles described in Scheme VA or VB may bereduced under standard conditions, such as hydrogenation with apalladium catalyst, to provide the corresponding chiral aminointermediate II. Such intermediates may be subsequently coupled withcompounds of type III as previously described to provide a chiralintermediate which can be deprotected to give diastereomerically purecompounds of formula Ia.

An additional approach and corresponding synthetic scheme for thepreparation of compounds of the instant invention is provided below inScheme VI:

Pharmaceutically active compounds of formula I include at leastcompounds of formula IA, IB, Id, and Ia′ as described herein.

Compounds of formula I may be conveniently screened for growth hormonesecretagogue activity. A typical assay may employ pituitary cellsestablished in culture, followed by a challenge with the variouscompounds of formula I, and the levels of growth hormone determinedaccordingly. Growth hormone levels may be calculated using variousradioimmunoassay techniques known to those of skill in the art.Screening of compounds for growth hormone secretagogue activity mayconveniently be scaled up for high throughput screening.

The invention further encompasses methods employing the pharmaceuticallyacceptable salts of the compounds defined by formula I. Althoughgenerally neutral, a compound of this invention can possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

The term “pharmaceutically acceptable salt” as used herein refers tosalts of the compounds of formula I which are substantially non-toxic toliving organisms. Typical pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid oran inorganic base. Such salts are known as acid addition and baseaddition salts.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, γ-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate, mesylate, and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and methanesulfonic acid.

Salts of amine groups may also comprise quaternary ammonium salts inwhich the amino nitrogen carries a suitable organic group such as analkyl, alkenyl, alkynyl, or aralkyl moiety.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

It should be recognized that the particular counterion forming a part ofany salt of this invention is not of a critical nature, so long as thesalt as a whole is pharmacologically acceptable and as long as thecounterion does not contribute undesired qualities to the salt as awhole.

This invention further encompasses methods employing pharmaceuticallyacceptable solvates of the compounds of Formula I. Many of the formula Icompounds can combine with solvents such as water, methanol, ethanol andacetonitrile to form pharmaceutically acceptable solvates such as thecorresponding hydrate, methanolate, ethanolate and acetonitrilate.

This invention also encompasses methods employing the pharmaceuticallyacceptable prodrugs of the compounds of formula I. A prodrug is a drugwhich has been chemically modified and may be biologically inactive atits site of action, but which may be degraded or modified by one or moreenzymatic or other in vivo processes to the parent bioactive form. Thisprodrug should have a different pharmacokinetic profile than the parent,enabling easier absorption across the mucosal epithelium, better saltformation or solubility, or improved systemic stability (an increase inplasma half-life, for example).

Typically, such chemical modifications include:

1) ester or amide derivatives which may be cleaved by esterases orlipases;

2) peptides which may be recognized by specific or nonspecificproteases; or

3) derivatives that accumulate at a site of action through membraneselection of a prodrug form or a modified prodrug form; or anycombination of 1 to 3, supra. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in H, Bundgaard, Design of Prodrugs, (1985).

Suitable dosing ranges of compounds of formula I include 0.01 μg/kg/dayto 60 mg/kg/day. Representative pharmaceutical formulations containingcompounds of formula I are provided below.

Pharmaceutical formulations containing a growth hormone secretagogue asdescribed herein may also include an effective amount of agents havingtherapeutic activity as α-adrenergic antagonists, angiotensin IIantagonists, angiotensin-converting enzyme (ACE) inhibitors,β-adrenergic antagonists, antihypertensives, calcium channel blockers,diuretics, potassium channel opening vasodilators, renin inhibitors, andserotonin antagonists.

In addition, growth hormone secretagogues may be administered along withcardiac stimulants such as dobutamine and xamoterol andphosphodiesterase inhibitors including amrinone and milrinone.

Optionally, the active ingredient of the pharmaceutical formulations caninclude an anabolic agent in addition to at least one growth hormonesecretagogue or another composition which exhibits another activity, forexample an antibiotic growth promoting agent, or a corticosteroidemployed to minimize the catabolic side effects, or another compoundwhich enhances efficacy and minimizes side effects. Growth promoting andanabolic agents include TRH, diethylstilbesterol, estrogens,β-antagonists, theophilline, anabolic steroids, enkephalins, E seriesprostaglandins, retinoic acid, zeranol, and sulbenox.

The different forms of these additional therapeutic agents available aswell as the various utilities associated with same and the applicabledosing regimens are well known to those of skill in the art. The methodof administration of each additional therapeutic agent is consistentwith that known in the art.

Also included are compounds of formula I employed in the manufacture ofa medicament for use in treating or preventing congestive heart failure.

As used herein, the term “effective amount” means an amount of compoundof the instant invention which is capable of inhibiting, alleviating,ameliorating, treating, or preventing further symptoms in mammals,including humans, suffering from congestive heart failure.

By “pharmaceutically acceptable formulation” it is meant that thecarrier, diluent, excipients and salt must be compatible with the activeingredient (a compound of formula I) of the formulation, and not bedeleterious to the recipient thereof. Pharmaceutical formulations can beprepared by procedures known in the art. For example, the compounds ofthis invention can be formulated with common excipients, diluents, orcarriers, and formed into tablets, capsules, and the like. Examples ofexcipients, diluents, and carriers that are suitable for suchformulations include the following: fillers and extenders such asstarch, sugars, mannitol, and silicic derivatives; binding agents suchas carboxymethyl cellulose and other cellulose derivatives, alginates,gelatin, and polyvinyl pyrrolidone; moisturizing agents such asglycerol; disintegrating agents such as agar agar, calcium carbonate,and sodium bicarbonate; agents for retarding dissolution such asparaffin; resorption accelerators such as quaternary ammonium compounds;surface active agents such as cetyl alcohol, glycerol monostearate;adsorptive carriers such as kaolin and bentonite; and lubricants such astalc, calcium and magnesium stearate and solid polyethylene glycols.Final pharmaceutical forms may be: pills, tablets, powders, lozenges,syrups, aerosols, saches, cachets, elixirs, suspensions, emulsions,ointments, suppositories, sterile injectable solutions, or sterilepackaged powders, and the like, depending on the type of excipient used.

Additionally, the compounds of this invention are well suited toformulation as sustained release dosage forms. The formulations can alsobe so constituted that they release the active ingredient only orpreferably in a particular part of the intestinal tract, possibly over aperiod of time. Such formulations would involve coatings, envelopes, orprotective matrices which may be made from polymeric substances orwaxes.

The particular dosage of a compound required to treat, inhibit, orprevent the symptoms and/or disease of congestive heart failure in amammal, including humans, according to this invention will depend uponthe particular disease, symptoms, and severity. Dosage, routes ofadministration, and frequency of dosing is best decided by the attendingphysician. Generally, accepted and effective doses will be from 15 mg to1000 mg, and more typically from 15 mg to 80 mg. Such dosages will beadministered to a patient in need of treatment from one to three timeseach day or as often as needed for efficacy.

The formulations which follow are given for purposes of illustration andare not intended to be limiting in any way. The total active ingredientsin such formulations comprises from 0.1% to 99.9% by weight of theformulation. The term “active ingredient” means a growth hormonesecretagogue, including GRP-2 or a compound of formula I.

Formulation 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

Formulation 2

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

Formulation 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active mixture is mixed with the lactose and the mixture is added toa dry powder inhaling appliance.

Formulation 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10%solution in water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50-60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Formulation 5

Capsules, each containing 40 mg of medicament are made as follows:

Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0mg Magnesium stearate 1.0 mg Total 150.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

Formulation 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient 25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of medicament per 5.0 ml dose aremade as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 ml

The medicament, sucrose and xanthan gum are blended, passed through aNo. 10 mesh U.S. sieve, and then mixed with a previously made solutionof the microcrystalline cellulose and sodium carboxymethyl cellulose inwater. The sodium benzoate, flavor, and color are diluted with some ofthe water and added with stirring. Sufficient water is then added toproduce the required volume.

Formulation 8

Capsules, each containing 15 mg of medicament, are made as follows:

Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0mg Magnesium stearate 3.0 mg Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 425 mg quantities.

Formulation 9

An intravenous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 250.0 mg Isotonic saline 1000 ml

Formulation 10

A topical formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g LiquidParaffin 20 g White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

Formulation 11

Sublingual or buccal tablets, each containing 10 mg of activeingredient, may be prepared as follows:

Quantity Ingredient Per Tablet Active Ingredient  10.0 mg Glycerol 210.5mg Water 143.0 mg Sodium Citrate  4.5 mg Polyvinyl Alcohol  26.5 mgPolyvinylpyrrolidone  15.5 mg Total 410.0 mg

The glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous stirring andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the solution is cooled to about 50-55° C. and themedicament is slowly admixed. The homogenous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 2-4 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices or patches. Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, for example, U.S.Pat. No. 5,023,252, the disclosure of which is herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, the disclosure of which is hereinincorporated by reference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionswhich can transiently open the blood-brain barrier.

The following Examples are provided to better elucidate the practice ofthe present invention and should not be interpreted in any way as tolimit the scope of same. Those skilled in the art will recognize thatvarious modifications may be made while not departing from the spiritand scope of the invention. All publications and patent applicationsmentioned in the specification are indicative of the level of thoseskilled in the art to which this invention pertains.

EXAMPLES PART 1

To a solution of boc-(OBz)-D-Ser-OH (25.0 g, 84.7 mmol) stirring inanhydrous N,N-dimethylformamide (500 mL) at room temperature was addedsodium bicarbonate (14.2 g, 169 mmol) followed by methyl iodide (26.4mL, 424 mmol). After 18 h, the reaction mixture was concentrated toapproximately 100 mL. Ethyl acetate was added and the mixture washedwith aqueous sodium bicarbonate and brine. The organic extract was driedand concentrated to give the desired compound (25 g, 96%) as a lightyellow oil: ¹H NMR (300 MHz, CDCl₃) d 1.45 (s, 9H), 3.70 (m, 1H), 3.75(s, 3H), 3.85 (m, 1H), 4.50 (m, 3H), 7.30 (m, 5H); MS (FD) m/e 310;Anal. calc'd for C₁₆H23NO₅: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.31;H, 7.49; N, 4.43.

To a solution of a compound of Preparation 1 (5.0 g, 16 mmol) stirringin dichloromethane (25 mL) and anisole (1 mL) at 0° C. was addedtrifluoroacetic acid. After 4 h at room temperature, saturated sodiumbicarbonate solution was added and the mixture extracted with ethylacetate. The combined organic extracts were washed with brine, driedover sodium sufate, and concentrated. The crude product was used in thenext step without further purification.

To a solution of a compound of Preparation 2 (65.4 mmol),boc-α-aminoisobutyric acid (13.2 g, 65.4 mmol), 1-hydroxybenzotriazole(8.8 g, 65.4 mmol), and N,N-diisopropylethylamine (22.8 mL, 130.7 mmol)stirring in dichloromethane (500 mL) at 0° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (12.3 g, 71.9 mmol). After18 h, ethyl acetate and saturated ammonium chloride were added and themixture extracted with ammonium chloride, sodium bicarbonate, and brine.The organic extracts were dried over sodium sulfate and concentated.Purification by silica gel chromatography (25% ethyl acetate/hexanes)yielded the desired compound (21.6 g, 83%) as a white solid: ¹H NMR (300MHz, CDCl₃) d 1.39 (s, 9H), 1.48 (s, 6H), 3.62 (dd, J=3.4, 9.1 Hz, 1H),3.70 (s, 3H), 3.85 (dd, J=3.4, 9.1 Hz, 1H), 4.48 (dd, J=12.5, 22.7 Hz,2H), 4.75 (m, 1H), 4.92 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.35 (m, 5H);MS (FD) m/e 395; Anal. calcl'd for C₂₀H₃₀N₂O₆: C, 60.90; H, 7.67; N,7.10. Found: C, 61.02; H, 7.78; N, 7.10.

To a solution of a compound of Preparation 3 (5.30 g, 13.4) stirring indioxane (100 mL)/water (50 mL) at room temperature was added lithiumhydroxide (2.80 g, 67.3 mmol). After 18 h, water was added and thesolution concentrated. The resulting mixture was extracted with diethylether. Sodium chloride was added to the aqueous layer and the pHadjusted to 3.5 with 1 N HCl. The resulting mixture was extracted withethyl acetate and the combined organic extracts dried over sodiumsulfate then concentrated to yield the title compound (4.40 g, 86%) as awhite foam: 1H NMR (300 MHz, CDCl₃) d 1.39 (s, 9H), 1.45 (s, 3H), 1.47(s, 3H), 3.68 (m, 1H), 3.95 (m, 1H), 4.54 (s, 2H), 4.70 (m, 1H), 5.51(bs, 1H), 7.18 (d, J=9.1 Hz, 1H), 7.25 (m, 5H), 9.90 (bs, 1H); MS (FD)m/e 381; Anal. calcl'd for C₁₉H₂₈N₂O₆: C, 59.99; H, 7.42; N, 7.36.Found: C, 59.74; H, 7.26; N, 7.30.

To a solution of α-bromophenylacetic acid (100 g, 466 mmol) stirring inabsolute ethanol (500 mL) at room temperature was addedp-toluenesulfonic acid monohydrate (10 g, 53 mmol). This solution washeated to reflux and, after 8 h, concentrated to dryness. The resultingresidue was dissolved in ethyl acetate, washed with saturated aqueoussodium bicarbonate, brine, dried over sodium sulfate, filtered, andconcentrated to yield 77 g (68%) of the desired product as an orangeoil: ¹H-NMR is consistent with structure; MS (FD) 241.9, 243.9.

To a slurry of sodium hydride (13.6 g of a 60% dispersion in mineraloil, 341 mmol) stirring in N,N-dimethylformamide (240 mL) was carefullyadded 4-nitroimidazole (38.6 g, 341 mmol) such that the temperatureduring the addition was maintained below 40° C. This resulting slurrywas stirred for 1 h and then cooled to 5° C. To this mixture was slowlyadded BX8-MEZ-148 (76 g, 310 mmol) at a rate such that the reactiontemperature was maintained below 20° C. After 4 h, the reaction wasconcentrated and subsequently extracted with ethyl acetate. The combinedorganic extracts were filtered, washed with water, brine, dried oversodium sulfate, filtered and concentrated. The resulting residue waspurified by silica gel chromatography (methanol/chloroform gradient) toyield the 60.1 g (70%) of the desired product as a white solid:

¹H-NMR is consistent with structure; MS (FD) 275 (M+); Anal. Cal'd. for:C, 56.73; H, 4.73; N, 15.27. Found: C, 56.48;

H, 4.78; N, 15.08.

To a suspension of 5% Pd/C (0.85 g) and a compound of Preparation 6(2.13 g, 7.21 mmol) stirring in dioxane (50 mL) at room temperature wasadded hydrogen (g) (35 psi) on a Parr apparatus. After 4 h, the mixturewas purged with nitrogen, celite added, and the solution filteredthrough a pad of celite. To the resulting filtrate, under nitrogenatmosphere, was added a compound of Preparation 4 (2.74 g, 7.21 mmol),1-hydroxybenzotriazole (0.97 g, 7.21 mmol), N,N-diisopropylethylamine(2.5 mL, 14.4 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(1.36 g, 7.93 mmol). After 18 hours, ethyl acetate was added and themixture washed with saturated aqueous ammonium chloride, saturatedaqueous sodium bicarbonate, and brine. The organic extract was driedover sodium sulfate and concentrated. Purification by silica gelchromatography (5% methanol/dichloromethane) yielded the title compound(1.25 g, 29%) as a yellow foam: ¹H NMR (300 MHz, CDCl₃) d 1.30 (t, J=6.9Hz, 3H), 1.40 (s, 9H), 1.42 (s, 3H), 1.51 (s, 3H), 3.60 (dd, J=5.1, 9.7Hz, 1H), 4.05 (m, 1H), 4.28 (m, 2H), 4.54 (dd, J=14.08, 26.3 Hz, 2H),4.62 (m, 1H), 5.08 (bs, 1H), 5.82 (s, 1H), 7.12 (d, J=11.5 Hz, 1H), 7.35(m, 12H), 9.75 (bs, 1H); MS (FD) m/e 607; Anal. calcl'd for C₃₂H₄₁N₅O₇:C, 63.29; H, 6.80; N, 11.52. Found: C, 63.07; H, 6.81; N, 11.74.

To a solution of a compound of Preparation 7 (5.3 g, 8.75) stirring indioxane (50 mL)/water (25 mL) at room temperature was added lithiumhydroxide (0.73 g, 17.50 mmol). After 20 min, water was added and thereaction concentrated to approximately 30 mL. The resulting mixture wasextracted with diethyl ether and the aqueous layer saturated with sodiumchloride then adjusted to pH 3.5 with 1 N HCl. The mixture was extractedwith ethyl acetate and the combined organic extracts dried over sodiumsulfate and concentrated to yield the title compound (4.90 g, 97%) as alight orange foam: ¹H NMR (300 MHz, CDCl₃) d ; MS (FD) m/e; Anal. calc'dfor: C,; H,; N. Found: C,; H,; N,.

To a solution of a compound of Preparation 8 (2.09 g, 3.61 mmol),pyrrolidine (0.30 mL, 3.61 mmol), and 1-hydroxybenzotriazole (0.54 g,3.97 mmol) stirring in anhydrous DMF (50 mL) at 0° C. was added1,3-dicyclohexyl carbodiimide (0.82 g, 3.97 mmol). After 18 hours atroom temperature, the reaction was concentrated, dissolved indichloromethane, filtered, and concentrated. Purification by silica gelchromatography (5% methanol/dichloromethane) yielded the title compound(1.74 g, 76%) as a light orange solid: ¹H NMR (300 MHz, CDCl₃) d 1.41(s, 9H), 1.43 (s, 3H), 1.52 (s, 3H), 2.88 (m, 4H), 3.42 (m, 1H), 3.50(m, 4H), 4.08 (m, 1H), 4.55 (dd, J=14.9, 27.4 Hz, 2H), 4.70 (m, 1H),4.96 (d, J=4.0 Hz, 1H), 5.86 (s, 1H), 7.15 (d, J=6.9 Hz, 1H), 7.35 (m,12H), 9.28 (bs, 1H); MS (FD) m/e 632; Anal. calc'd for C₃₄H₄₄N₆O₆: C,64.54; H, 7.01; N, 13.28. Found: C, 63.48; H, 6.95; N, 12.19.

Example 1

To a solution of a compound of Preparation 9 (1.00 g, 1.58 mmol) andanisole (0.3 mL) stirring in anhydrous dichloromethane (12 mL) at 0° C.was added trifluoroacetic acid (3 mL) and the reaction mixture warmed toroom temperature. After 4 h, the dichloromethane was removed in vacuoand excess diethyl ether added. After 20 min, the reaction mixture wasfiltered to yield the title compound (1.02 g, 85%) as a white solid: ¹HNMR (300 MHz, CDCl₃) d 1.60 (s, 6H), 1.90 (m, 4H), 3.08 (m, 1H), 3.58(m, 3H), 3.88 (m, 2H), 4.52 (m, 2H), 4.72 (m, 1H), 6.10 (m, 2H), 7.25(m, 6H), 7.46 (m, 5H), 7.70 (m 1H), 8.00 (m, 1H), 8.40 (m, 1H), 11.15(m, 1H ); MS (FD) m/e 532 (M-2TFA); Anal. calc'd for C₃₃H₃₈F₆N₆O₈: C,52.10; H, 5.03; N, 11.05. Found: C, 51.54; H, 5.25; N, 11.21.

To a slurry of d,1-α-amino-4-phenylbutyric acid (20.0 g, 111 mmol)stirring in 3N sulfuric acid (200 mL) at 0° C. was added finely groundpotassium bromide (48 g, 403 mmol). This slurry was cooled to −10° C.,then a solution of sodium nitrite (11.0 g, 160 mmol in water (75 mL))was added dropwise. The resulting solution was stirred for 4 h whileslowly warming to ambient temperature. The resulting precipitate wasfiltered to give 20.0 g of a yellow solid. To a solution of the yellowsolid (18.8 g, 80 mmol) in absolute ethanol (400 mL) was addedp-toluenesulfonic acid monohydrate (4.6 g, 24 mmol). This solution wasrefluxed for 4 h, filtered and concentrated. The resulting residue waspurified by silica gel chromatography (ethyl acetate/hexanes gradient)to give 7.2 g (24%) of the desired product as a clear oil. ¹H-NMR isconsistent with structure; MS (FD) 269, 27

To a slurry of sodium hydride (1.0 g of a 60% dispersion in mineral oil,24 mmol) stirring in N,N-dimethylformamide (200 mL) at ambienttemperature was carefully added a solution of 4-nitroimidazole (5.7 g,20 mmol). This mixture was cooled to 0° C. and a solution of a compoundof Preparation 10 (15.2 g, 60 mmol) in N,N-dimethylformamide (10 mL) wasadded. After 16 h, the mixture was slowly warmed to ambient temperature,concentrated, and the resulting residue extracted with chloroform. Thecombined organic extracts were washed with water, brine, dried oversodium sulfate, filtered and concentrated. The resulting residue waspurified by silica gel chromatography (chloroform) to give 5.0 g (82%)of the desired product as a clear oil. ¹H-NMR is consistent withstructure; MS (FD) 303 (M+); Anal. Calc'd for: C, 59.40; H, 5.65; N,13.85. Found: C, 59.73; H, 5.71; N, 13.40.

To a solution of a compound of Preparation 11 (4.24 g, 14 mmol) stirringin tetrahydrofuran (30 mL) and ethanol (30 mL) at room temperature wasadded 2N NaOH (35 mL, 70 mmol). After 1 h, this mixture was treated with5N HCl until pH=2.5. Ethyl acetate (30 mL) and water (30 mL) were addedand the resulting solution was extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated to give 3.8 g (98%) of the desiredproduct as a yellow oil: ¹H-NMR is consistent with structure; MS (FD)276 (M+).

To a solution of a compound of Preparation 12 (3.8 g, 14 mmol),1-proline methylester (1.8 g, 14 mmol) and 1-hydroxybenzotriazolehydrate (2.1 g, 15 mmol) stirring in N,N-dimethylformamide (150 mL) atroom temperature was added 1,3-dicyclohexylcarbodiimide (3.2 g, 15.4mmol). After 16 h, the mixture was concentrated and the resultingresidue partitioned between ethyl acetate and water. The combinedorganic extracts were washed with water, brine, dried over sodiumsulfate, and concentrated. The resulting orange oil was purified bysilica gel chromatography (methanol/chloroform gradients) to give 3.8 g(70%) of the desired product as a yellow oil: ¹H-NMR is consistent withstructure; MS (FD) 386.2 (M+).

To a slurry of 10% Pd/C in dioxane (10 mL) was added a solution of acompound of Preparation 13 (2.4 g, 6.2 mmol) in dioxane (100 mL). Themixture was then treated with hydrogen gas (40 psi) on a Parr apparatus.After 5 h, an amount of 10% Pd/C (0.5 g) in dioxane (10 mL) was added.The mixture was hydrogenated for 4 h then carefully filtered throughcelite. To the resulting filtrate was added a compound of Preparation 4(2.4 g, 6.2 mmol), 1-hydroxybenzotriazole hydrate (0.92 g, 6.8 mmol),followed by 1,3-dicyclohexylcarbodiimide (1.4 g, 6.8 mmol). After 16 h,the reaction was concentrated and the resulting residue extracted withethyl acetate. The combined organic extracts were washed with saturatedaqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered,and concentrated. Purification silica gel chromatography(methanol/chloroform gradient) gave 2.2 g (50%) of the desired productas a tan foam: ¹H-NMR is consistent with structure; MS (FD) 718.7 (M+);Anal Calc'd for: C, 63.49; H, 7.01; N, 11.69. Found: C, 63.30; H, 6.91;N, 11.84.

Example 2

To a solution of a compound of Preparation 14 (2.1 g, 3.0 mmol) stirringin dichloromethane (25 mL) was added trifluoroacetic acid (8 mL, 104mmol). After one h, water (25 mL) was added and the solution wasquenched carefully with sodium carbonate, then extracted withchloroform. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. To a solution of theresulting residue in diethyl ether (40 mL) was added a saturatedsolution of HCl in diethyl ether (40 mL). The resulting slurry wasconcentrated to dryness to yield 1.6 g (80%) of the desired product as atan foam: ¹H-NMR is consistent with structure; MS (FD) 618.3 (M+); Anal.Calc'd. for: C, 57.31; H, 6.41; N, 12.15. Found: C, 57.52; H, 6.19; N,12.04. IR (KBr) 2954, 1743, 1656, 1559, 1496, 1453 cm⁻¹.

Reaction of d,1-α-phenylalanine (20.0 g, 120 mmol), potassium bromide(48 g, 400 mmol), sodium nitrite (11.0 g, 160 mmol), water (75 mL), 3Nsulfuric acid (200 mL), p-toluenesulfonic acid monohydrate (5.7 g, 30mmol) and absolute ethanol (500 mL) according to Preparation 10 gave18.0 g (70%) of the desired product as a colorless oil: ¹H-NMR isconsistent with structure; MS (FD) 256, 258.

Reaction of a compound of Preparation 15 (15.22 g, 60 mmol), sodiumhydride (2.84 g of a 60% dispersion in mineral oil, 72 mmol),4-nitroimidazole (8.1 g, 72 mmol) in N,N-dimethylformamide (400 mL)according to Preparation 11 gave 9.5 g (55%) of the desired product as ayellow foam: ¹H-NMR is consistent with structure; MS (FD) 289.1 (M+);Anal. Calc'd. for: C, 58.13; H, 5.23; N, 14.53. Found: C, 58.40; H,5.17; N, 14.24.

Reaction of a compound of Preparation 16 (3.3 g, 12.0 mmol), 2N NaOH (30mL, 60 mmol) in ethyl acetate (30 mL)/ethanol (30 mL) accordingPreparation 12 gave 2.85 g (90%) of the desired product as a whitesolid: ¹H-NMR is consistent with structure; MS (FD) 262 (M+); Anal.Calc'd. for: C, 55.17; H, 4.24; N, 16.09. Found: C, 55.14; H, 4.24; N,15.94.

Reaction of a compound of Preparation 17 (2.8 g, 11.0 mmol), 1-prolinemethylester (1.4 g, 11.0 mmol), 1-hydroxybenzotriazole hydrate (1.63 g,12.1 mmol), and 1,3-dicyclohexylcarbodiimide (2.5 g, 12.1 mmol) inN,N-dimethylformamide (150 mL according to Preparation 13 gave 3.2 g(70.4%) of the desired product as a white solid: ¹H-NMR is consistentwith structure; MS (FD) 372 (M+).

Reaction of a compound of Preparation 18 (0.6 g, 1.6 mmol), 5% Pd/C(0.66 g) in ethyl acetate (50 mL), ethanol (50 mL) and dichloromethane(4 mL), a compound of Preparation 4 (0.46 g, 1.2 mmol),1-hydroxybenzotriazole hydrate (0.18 g, 1.3 mmol) and1,3-dicyclohexylcarbodiimide (0.27 g, 1.3 mmol) in N,N-dimethylformamide(100 mL) according to Preparation 14 gave 0.29 g (34%) of the desiredproduct as a tan foam: ¹H-NMR is consistent with structure; MS (FD)704.5 (M+).

Example 3

Reaction of a compound of Preparation 19 (0.23 g, 0.33 mmol),trifluoroacetic acid (4.0 mL, 24 mmol) in dichloromethane (12 mL),followed by treatment with HCl/ethyl acetate solution (40 mL), accordingto Example 2 gave 0.17 g (77%) of the desired product as a white foam:¹H-NMR is consistent with structure; MS (FD) 604 (M+); Anal. Calc'd for:C, 56.72; H, 6.25; N, 12.40. Found: C, 56.53; H, 6.31; N, 12.19. IR(KBr) 2931.09, 1743.64, 1653.48, 1533.67, 1453.73 (cm⁻¹).

Reaction of ethylbromoacetate (4.9 mL, 44 mmol), 4-nitroimidazole (5.00g, 44 mmol) and potassium carbonate (12.2 g, 88 mmol) at ambienttemperature in N,N-dimethylformamide (50 mL) according to Preparation 3from Examples Part 2A gave 7.77 g (88%) of the desired product as anorange solid: ¹H-NMR was consistent with structure; MS (FD) 199 (M+);Anal. Calc'd for: C, 42.21; H, 4.55; N, 21.10. Found: C, 42.51; H, 4.66;N, 21.24.

Reaction of a compound of Preparation 20 (2.00 g, 10.0 mmol) and 2N NaOH(30 mL, 60 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) accordingPreparation 12 gave 1.3 g (76%) of the desired product as a tan solidwhich is carried on without further purification.

Reaction of a compound of Preparation 21 (1.20 g, 7.0 mmol), 1-prolinemethylester hydrochloride (1.27 g, 8.4 mmol), 1-hydroxybenzotriazolehydrate (1.04 g, 8.4 mmol), triethylamine (1.95 mL, 14.0 mmol) and1,3-dicyclohexylcarbodiimide (1.6 g, 8.4 mmol) in N,N-dimethylformamideaccording to Preparation 13 gave 0.6 g (30%) of the desired compound asa tan semi-solid: ¹H-NMR is consistent with structure; MS (FD) 282 (M+).

Hydrogenation of a compound of Preparation 22 (0.47 mg, 1.7 mmol) and 5%Pd—C (0.15 g) in ethyl acetate (20 mL)/ethanol (20 ml) followed bytreatment with 1-hydroxybenzotriazole hydrate (225 mg, 1.7 mmol),1,3-dicyclohexylcarbodiimide (340 mg, 1.7 mmol) and 368979 (633 mg, 1.7mmol) according to Preparation 14 gave 0.45 g (39%) of the desiredproduct: ¹H-NMR is consistent with structure; MS (FD) 614 (M+).

Example 4

Reaction of a compound of Preparation 23 (0.40 g, 0.65 mmol) andtrifluoroacetic acid (5 mL, 64 mmol) in dichloromethane (20 mL)according to Example 2 gave 0.22 g (67%) of the desired product as anoff-white solid: ¹H-NMR is consistent with structure; MS (FD) 514 (M+);Anal. Calc'd for: C, 58.35; H, 6.66; N, 16.33. Found: C, 58.25; H, 6.40;N, 16.16.

Reaction of 5-nitroindole (3.0 g, 18.5 mmol), α-bromophenylacetic acidethylester (4.5 g, 18.5 mmol), and sodium hydride (0.8 g, 20 mmol, 60%dispersion in mineral oil) in N,N-dimethylformamide (75 mL) according toPreparation 1 gave 3.9 g (65%) of the desired product: ¹H-NMR isconsistent with structure; MS (FD) 324 M+; Anal. Calc'd for: C, 66.66;H, 4.97; N, 8.64. Found: C, 66.80; H, 5.11; N, 8.81.

Reaction of a compound of Preparation 24 (2.0 g, 6.2 mmol) and 2N NaOH(50 mL, 100 mmol) in tetrahydrofuran (10 mL)/ethanol (8 mL) according toPreparation 12 gave 1.4 g (76%) of the desired product as a yellowsolid: ¹H-NMR is consistent with structure; MS (FD) 296 (M+); Anal.Calc'd for: C, 64.86; H, 4.08; N, 9.45. Found: C, 64.60; H, 4.14; N,9.29.

Reaction of a compound of Preparation 25 (1.0 g, 5.7 mmol),1-hydroxybenzotriazole hydrate (0.85 g, 6.3 mmol), 1-proline methylesterhydrochloride (1.03 g, 6.3 mmol), triethylamine (1.6 mL, 11.4 mmol) and1,3-dicyclohexylcarbodiimide (1.3 g, 6.3 mmol) in N,N-dimethylformamide(25 mL) according to Preparation 13 gave 1.35 g (58%) of the desiredproduct as yellow solid: ¹H-NMR is consistent with structure; MS (FD)407 (M+); Anal. Calc'd for: C, 64.86; H, 5.20; N, 10.31. Found: C,65.20; H, 5.50; N, 10.10.

Hydrogenation of a compound of Preparation 26 (0.41 g, 1.0 mmol) with 5%Pd—C (0.08 g) in ethanol (25 mL)/ethyl acetate (25 mL) followed bytreatment with 1-hydroxybenzotriazole hydrate (0.15 g, 1.1 mmol),1,3-dicyclohexylcarbodiimide (0.23 g, 1.1 mmol) and 368979 (0.42 g, 1.1mmol) according to Preparation 14 gave 0.38 g (51%) of the desiredproduct: ¹H-NMR is consistent with structure; MS (FD) 739.7 (M+)

Example 5

Reaction of a compound of Preparation 27 (0.38 g, 0.51 mmol) andtrifluoroacetic acid (2 mL, 26 mmol) in dichloromethane (10 mL)according to Example 2 gave 0.125 g (38%) of the desired product: ¹H-NMRis consistent with structure; MS (FD) 639 (M+); Anal. Calc'd for 1 H₂O:C, 65.74; H, 6.59; N, 10.65. Found: C, 65.75; H, 6.42; N, 10.98.

To a solution of a compound of Preparation 6 (27 g, 98 mmol) stirring intetrahydrofuran (60 mL) and absolute ethanol (60 mL) at ambienttemperature was added 2N NaOH (250 mL, 500 mmol). After 3.5 h, themixture was washed with diethyl ether and the organic extractsubsequently washed with water. The combined aqueous extracts wereacidified and the resulting mixture extracted with ethyl acetate. Thecombined organic extracts were washed once with brine, dried over sodiumsulfate, filtered, and concentrated to give 24.2 g (75%) of the desiredproduct as a tan solid: ¹H-NMR was consistent with structure; MS (FD)246.9 (M+); Anal. Calc'd for: C, 53.44; H, 3.67; N, 17.00. Found: C,53.71; H, 3.67; N, 16.83. mp=218-221° C.

To a slurry of a compound of Preparation 28 (8.15 g, 33 mmol) stirringin dichloromethane (100 mL) was added oxalyl chloride (11.5 mL, 130mmol) and N,N-dimethylformamide (2 drops). After 90 min at ambienttemperature, the mixture was concentrated and the residue was dissolvedin dichloromethane (40 mL). The resulting solution was added aN,N-diisopropylethylamine (6.5 mL, 360 mmol) and 1-prolinemethylester(3.9 g, 20 mmol) in dichloromethane (4 mL). After 2 h at ambienttemperature, the mixture was extracted with ethyl acetate and thecombined organic extracts washed with water, brine, dried over sodiumsulfate, filtered, and concentrated. The resulting residue was purifiedby silica gel chromatography (ethyl acetate/hexanes) to give 10.7 g(71%) of the desired product as tan foam: ¹H-NMR is consistent withstructure; Anal. Calc'd for: C, 56.98; H, 5.06; N, 15.63. Found: C,56.75; H, 5.14; N, 15.44. Mp, 103-111° C.

To a slurry of 5% Pd/C (0.28 g) in ethyl acetate (30 mL) was added asolution of a compound of Preparation 29 (1.0 g, 2.8 mmol) in ethanol(100 mL). The mixture was hydrogenated at 40 psi on a Parr apparatus.After 25 min, additional 5% Pd/C (0.5 g) was added and the mixturesusbsequently hydrogenated for 45 min, then filtered through celite andconcentrated. To a slurry of the resulting residue inN,N-dimethylformamide (100 mL) was added boc-d-benzyloxyserine (0.62 g,2.1 mmol), 1-hydroxybenzotriazole hydrate(0.31 g, 2.3 mmol) followed by1,3-dicyclohexylcarbodiimide (0.48 g, 2.3 mmol). After 48 h, the mixturewas filtered and concentrated and the residue purified by radialchromatography (silica gel, methanol/chloroform gradient). The resultingproduct was dissolved in ethyl acetate and washed with water, dried oversodium sulfate, filtered, and concentrated to give 0.5 g (30%) of thedesired product as a tan foam: ¹H-NMR is consistent with structure; MS(FD) 605 (M+).

To a solution of a compound of Preparation 30 (3.1 g, 5.1 mmol) stirringin methanol (200 mL) at room temperature was added 5N HCl (51.0 mmol).After 16 h, the residue was partitioned between ethyl acetate and waterand extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried over sodium sulfate, filtered and concentratedto give 2.1 g (81%) of the desired compound as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 506 (M+); Anal. Calc'd. for: C,64.14; H, 6.18; N, 13.85. Found: C, 63.92, H, 6.18; N, 13.56.

To a solution of a compound of Preparation 31 (2.1 g, 4.2 mmol) stirringin N,N-dimethylformamide (200 mL) was added Boc-α-aminoisobutyric acid(0.85 g, 4.2 mmol), 1-hydroxybenzotriazole hydrate(0.62 g, 4.6 mmol).After 16 h, mixture was concentrated to dryness and the resultingresidue extracted with ethyl acetate. The combined organic extracts werewashed with water, brine, dried over sodium sulfate, filtered, andconcentrated. Purification by silica gel chromatography(methanol/chloroform) gave 2.3 g (80%) of the desired product as a tanfoam: ¹H-NMR is consistent with structure; MS (FD) 690 (M+).

Example 6

To a solution of the compound of Preparation 32 (1.75 g, 2.5 mmol)stirring in dichloromethane (190 mL) was added trifluoroacetic acid (63mL, 780 mmol). After 1 h, the mixture was poured carefully intosaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered, and concentrated. The residue was dissolved in ethylacetate (250 mL) and subsequently treated with a saturated solution ofHCl in ethyl acetate (100 mL). The resulting mixture was concentrated todryness, triturated with diethyl ether, and filtered to give 0.6 g (38%)of the desired product as a tan solid: ¹H-NMR is consistent withstructure; MS (FD) 590 (M+); Anal. Calc'd for: C, 54.60; H, 5.92; N,12.33. Found: C, 54.47; H, 5.72; N, 12.16. IR (KBr) 3164, 3030, 2978,2952, 2878, 1743, 1664, 1531, 1456, 1436, 1498, 1197, 1179 cm⁻¹.

The optically enriched S-isomer was isolated by selectivecrystallization (ethyl acetate/hexanes) of a compound of Preparation 29to give 1.3 g of the desired isomer: ¹H-NMR is consistent withstructure; MS (FD) 358 (M+); Anal. Calc'd for: C, 56.98; H, 5.06; N,15.63. Found: C, 57.22; H, 4.87; N, 15.34. mp=114-118° C.

Hydrogenation of a compound of Preparation 29 (1.0 g, 2.8 mmol) and 5%Pd/C (0.756 g) in absolute ethanol (20 mL)/ethyl acetate (20 mL),followed by treatment of the resulting mixture withboc-d-benzyloxyserine (0.83 g, 2.8 mmol), 1-hydroxybenzotriazole hydrate(0.42 g, 3.4 mmol) and 1,3-dicyclohexylcarbodiimide (0.64 g, 3.1 mmolaccording to Preparation 1 gave 0.69 g (41%) of the desired product as acrystalline solid. Purification by silica gel chromatography(methanol/chloroform) followed by re-crystalization from ethyl acetate:¹H-NMR is consistent with structure; MS (FD) 605 (M+); Anal. Calc'd.for: C, 63.46; H, 6.49; N, 11.56. Found: C, 63.61; H, 6.31; N, 11.38;mp=184-186° C.

Reaction of a compound of Preparation 34 (0.61 g, 1.0 mmol) andtrifluoroacetic acid (1.7 mL, 22 mmol) in dichloromethane (40 mL)according to Preparation 1 gave 0.5 g (100%) of the desired product as afoam: ¹H-NMR is consistent with structure; MS (FD) 506 (M+); mp=55-60°C.

Reaction of a compound of Preparation 35 (0.5 g, 1 mmol),1-hydroxybenzotriazole hydrate (0.15 g, 1.1 mmol) and1,3-dicyclohexylcarbodiimide (0.23 g, 1.1 mmol) in N,N-dimethylformamide(15 mL) according to Preparation 32 gave 0.69 g (100%) of the desiredproduct as a foam: ¹H-NMR is consistent with structure; MS (FD) 690.2(M+); mp=81-84° C.

Example 7

Reaction of a compound of Preparation 36 (0.595 g, 0.95 mmol) andtrifluoroacetic acid (0.7 mL, 9.0 mmol) in dichloromethane (25 mL)according to Preparation 1 gave 0.37 g (75%) of the desired product as asolid: ¹H-NMR was consistent with structure; MS (FD) 590 (M+); Anal.Calc'd for: C, 63.04; H, 6.48; N, 14.23. Found: C, 62.98; H, 6.59; N,14.01. Mp, 156-159° C.

Reaction of a compound of Preparation 29 (2.63 g, 8.0 mmol),boc-1-benzyloxyserine (2.4 g, 8.0 mmol), 1-hydroxybenzotriazole hydrate(1.2 g, 8.8 mmol), 1,3-dicyclohexylcarbodiimide (1.8 g, 8.8 mmol) inN,N-dimethylformamide (250 mL) gave 2.4 g (50%) of the desired productas tan foam: ¹H-NMR is consistent with structure; MS (FD) 605 (M+).

Reaction of a compound of Preparation 37 (2.3 g, 3.8 mmol),trifluoroacetic acid (35 mL, 45 mmol) in dichloromethane (90 mL) gave1.4 g (74%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 506 (M+).

Reaction of a compound of Preparation 38 (1.1 g, 2.2 mmol),boc-α-aminoisobutyric acid (0.45 g, 2.2 mmol), 1-hydroxybenzotriazolehydrate (0.33 g, 2.4 mmol) and 1,3-dicyclohexylcarbodiimide (0.5 g, 2.4mmol) in N,N-dimethylformamide (100 mL) gave 0.84 g (55%) of the desiredproduct as a tan foam: ¹H-NMR is consistent with structure; MS (FD) 690(M+).

Example 8

Reaction of a compound of Preparation 39 (0.7 g, 1.0 mmol),trifluoroacetic acid (25 mL, 320 mmol) in dichloromethane, and followedby dissolution in ethyl acetate (100 mL) and treatment with ethylacetate saturated with HCl (100 mL) yielded 0.29 g (44%) of the desiredcompound as a white solid: ¹H-NMR is consistent with structure; MS (FD)590 (M+); Anal. Calc'd for: C, 56.11; H, 6.08; N, 12.66. Found: C,56.16; H, 5.92; N, 12.56. IR (KBr) 3163.75, 3031.15, 2952.46, 2876.38,1745.07, 1664.94, 1530.69, 1497.79, 1453.37, 1435.81, 1197.21, 1177.62,1094.93, 747.95, 701.04 cm⁻¹.

To a solution of a compound of Preparation 28 (1.0 g, 4.0 mmol),morpholine (0.35 mL, 4.0 mmol), 1-hydroxybenzotriazole hydrate (0.6 g,4.4 mmol) stirring in N,N-dimethylformamide (50 mL) at room temperaturewas added 1,3-dicyclohexylcarbodiimide (0.9 g, 4.4 mmol). After 16 h,the mixture was concentrated, and the residue extracted with ethylacetate. The combined organic extracts were filtered, washed withsaturated aqueous sodium bicarbonate, water, brine, dried over sodiumsulfate, filtered, and concentrated. The resulting residue was purifiedby silica gel chromatography (methanol/chloroform) to give 0.75 g (60%)of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (FD) 316 (M+).

To a slurry of 5% Pd/C (0.18 g) in ethyl acetate (5 mL) was carefullyadded a solution of a compound of Preparation 40 (0.67 g, 2.0 mmol) inethyl acetate (25 mL)/ethanol (25 mL). The resulting slurry was treatedwith hydrogen gas at 40 psi on a Parr apparatus. After 1 h, a slurry of5% Pd/C (0.18 g) in ethyl acetate (10 mL) was added to this mixture,followed by hydrogenation at 40 psi. After 1 h, the mixture was filteredthrough celite and concentrated. To the residue stirring inN,N-dimethylformamide (100 mL) was added a compound of Preparation 4(0.53 g, 1.4) and 1-hydroxybenzotriazole hydrate (0.21 g, 1.54 mmol)followed by 1,3-dicyclohexylcarbodiimide (0.32 g, 1.54 mmol). After 16 hat room temperature, the solution was concentrated and extracted withethyl acetate. The combined organic extracts were washed with water,brine, dried over sodium sulfate, filtered, and concentrated. Theresulting residue was purified by silica gel chromatography(methanol/chloroform) to yield 0.27 g (30%) of the desired product as atan foam: ¹H-NMR is consistent with structure; MS (FD) 448 (M+).

Example 9

To a solution of a compound of Preparation 41 (0.27 g, 0.42 mmol)stirring in dichloromethane (12 mL) at room temperature was addedtrifluoroacetic acid (4 mL, 51 mmol). After 1.5 h, water (40 mL) wasadded and the reaction mixture quenched carefully with solid sodiumbicarbonate. The resulting mixture was extracted with ethyl acetate andthe combined organic extracts washed with brine, dried over sodiumsulfate, filtered and concentrated. The concentrate was dissolved inethyl acetate (40 mL) and subsequently treated with a saturated solutionof HCl in ethyl acetate (40 mL). After 15 min, the mixture wasconcentrated to give 0.14 g (54%) of the desired product as a whitesolid: ¹H-NMR is consistent with structure; MS (FD) 548 (M+); Anal.Calc'd. for: C, 56.04; H, 6.16; N, 13.52. Found: C, 55.78; H, 6.11; N,13.27; IR (KBr) 2927, 2858.9, 1659.3, 1542.2, 1114.4 cm ⁻¹.

Reaction of a compound of Preparation 28 (1.0 g, 4.0 mmol), piperidine(0.4 mL, 4.0 mmol), 1-hydroxybenzotriazole hydrate (0.6 g, 4.4 mmol) and1,3-dicyclohexylcarbodiimide (0.9 g, 4.4 mmol) in N,N-dimethylformamide(50 mL) gave 0.95 g (75%) of the desired product as a tan foam: ¹H-NMRis consistent with structure; MS (FD) 314 (M+).

Hydrogenation of a compound of Preparation 42 (0.91 g, 2.9 mmol) inethyl acetate (50 mL)/ethanol (50 mL), 5% Pd/C (0.36 g) in ethyl acetate(5 mL) followed by reaction with a compound of Preparation 4 (0.95 g,2.5 mmol), 1-hydroxybenzotriazole hydrate (0.37 g, 2.75 mmol), and1,3-dicyclohexylcarcodiimide (0.57 g, 2.75 mmol) gave 0.43 g (25%) ofthe desired product as a tan foam: ¹H-NMR is consistent with structure;MS (FD) 646 (M+).

Example 10

Reaction of a compound of Preparation 43 (0.38 g, 0.59 mmol) andtrifluoroacetic acid (4 mL, 51 mmol) in dichloromethane (12 mL) followedby acidification with HCl gave 0.03 g (8.3%) of the desired product as atan solid: ¹H-NMR is consistent with structure; MS (FD) 546 (M+); IR(KBr) 3141, 2937, 2859, 1642, 1534, 1453, 1444 cm⁻¹.

To a slurry of 5% Pd/C (1.0 g) in ethyl acetate (25 mL) was added asolution of a compound of Preparation 6 (8.25 g, 30 mmol) in ethylacetate (25 mL)/absolute ethanol (25 mL). The slurry was hydrogenated at40 psi on a Parr apparatus. After 75 min, a slurry of 5% Pd/C (0.7 g) inethyl acetate (25 mL) was added to the reaction mixture. Afterhydrogenation at 40 psi for 1.5 h, the mixture was filtered throughcelite and concentrated. The concentrate was dissolved inN,N-dimethylformamide (500 mL) and boc-d-benzyloxyserine (9.0 g, 30.8mmol), 1-hydroxybenzotriazole hydrate (4.5 g, 33 mmol) and1,3-dicyclohexylcarbodiimide (6.8 g, 33 mmol) added. After 16 h atambient temperature, the mixture was concentrated and the residueextracted with ethyl acetate. The combined organic extracts were washedwith water, brine, dried over sodium sulfate, filtered, andconcentrated. Purification by silica gel chromatography(methanol/chloroform) gave 8.33 g (53%) of the desired product as a tansolid: ¹H-NMR is consistent with structure; MS (FD) 522 (M+); Anal.Calc'd. for: C, 64.35; H, 6.56; N, 10.72. Found: C, 64.59; H, 6.83; N,10.77.

To a solution of a compound of Preparation 44 (8.1 g, 15.5 mmol)stirring at room temperature in dichloromethane (75 mL) was addedtrifluoroacetic acid (25 mL, 320 mmol). After 50 min, the mixture wascarefully poured into a saturated aqueous solution of sodium bicarbonateand extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried over sodium sulfate, filtered and concentratedto give 6.5 g (99%) of the desired product as a tan solid. ¹H-NMR isconsistent with structure; MS (FD) 422 (M+).

To a solution of a compound of Preparation 45 (6.5 g, 15.0 mmol),boc-α-aminoisobutyric acid (3.05 g, 15.0 mmol), 1-hydroxybenzotriazolehydrate (2.23 g, 16.5 mmol) stirring in N,N-dimethylformamide (400 mL)at room temperature was added 1,3-dicyclohexylcarbodiimide (3.4 g, 16.5mmol). After 16 h, the mixture was concentrated and the resultingresidue extracted with ethyl acetate. The combined organic extracts werewashed with water, brine, dried over sodium sulfate, filtered, andconcentrated. Purification by silica gel chromatography(methanol/chloroform) gave 6.39 g (70%) of the desired product as a tanfoam: ¹H-NMR is consistent with structure; MS (FD) 607 (M+). Anal.Calc'd. for: C, 63.25; H, 6.80; N, 11.52. Found: C, 63.36; H, 6.92; N,11.59.

To a solution of a compound of Preparation 46 (6.04 g, 9.9 mmol)stirring in absolute ethanol (50 mL)/tetrahydrofuran (50 mL) at roomtemperature was added 1N NaOH (50 mL, 49.5 mmol). After 30 min, themixture was acidified with 1N HCl and extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered, and concentrated to give 5.4 g (94%) of the desiredproduct as a tan foam: ¹H-NMR is consistent with structure; MS (FD) 580(M+); Anal. Calc'd. for: C, 62.16; H, 6.43; N, 12.08. Found: C, 61.86;H, 6.29; N, 12.06.

To a solution of a compound of Preparation 47 (0.7 g, 1.2 mmol),N-methylamine hydrochloride (0.08 g, 1.2 mmol), triethylamine (0.5 mL,3.6 mmol), and 1-hydroxybenzotriazole hydrate (0.18 g, 1.32 mmol)stirring in N,N-dimethylformamide (50 mL) at room temperature was added1,3-dicyclohexylcarbodiimide (0.27 g, 1.32 mmol). After 16 h, themixture was concentrated and the resulting residue extracted with ethylacetate. The combined organic extracts were washed with water, brine,dried over sodium sulfate, filtered, and concentrated. Purification bysilica gel chromatography (methanol/chloroform) gave 0.25 g (35%) of thedesired product as a white solid: ¹H-NMR is consistent with structure;MS (FD) 592.4 (M+); Anal. Calc'd for 0.32 mol hydrate: C, 62.21; H,6.76; N, 14.04. Found: C, 62.17; H, 6.74; N, 14.19.

Example 11

To a slurry of a compound of Preparation 48 (0.2 g, 0.34 mmol) stirringin dichloromethane (12 mL) at room temperature was added trifluoroaceticacid (4 mL, 52 mmol). After 2 h, additional trifluoroacetic acid (4 mL,52 mmol) was added and the reaction was heated to reflux. After 7 h, themixture was cooled to room temperature, water (40 mL) added, followedexcess solid sodium bicarbonate. The mixture was extracted with ethylacetate and the combined organic extracts washed with brine, dried oversodium sulfate, filtered and concentrate. The resulting crude productwas dissolved in ethyl acetate (40 mL) and a saturated solution of HClin diethyl ether was added (40 mL). After 15 min, this slurry wasconcentrated to give 0.13 g (68%) of the desired product as a whitesolid: ¹H-NMR is consistent with structure; MS (FD) 492 (M+); Anal.Calc'd for: C, 55.22; H, 6.06; N, 14.86. Found: 55.33; H, 6.28; N,13.24; IR (KBr) 3224, 3061, 3032, 2962, 2936, 2873, 1678, 1636, 1538,1498, 1454, 1101 cm⁻¹.

Reaction of a compound of Preparation 47 (1.00 g, 580 mmol),hexamethyleneimine (0.2 mL, 1.7 mmol), 1-hydroxybenzotriazole hydrate(0.25 g, 1.9 mmol) and 1,3-dicyclohexylcarbodiimide (0.4 g, 1.9 mmol) inN,N-dimethylformamide (50 mL) as described in Preparation 4 gave 0.76 g(68%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 660.2 (M+); Anal. Calc'd for: C, 65.43; H, 7.32; N,12.02. Found: C, 65.92; H, 7.86; N, 11.71.

Example 12

Reaction of a compound of Preparation 49 (0.67 g, 1.0 mmol) andtrifluoroacetic acid (4 mL, 52 mmol) in dichloromethane (12 mL) for 1 hat ambient temperature, followed by acidification with HCl in ethylacetate, according to Preparation 4 gave 0.3 g (48%) of the desiredproduct as a white solid: ¹H-NMR is consistent with structure; MS (FD)560.4 (M); Anal. Calc'd for: C, 58.77; H, 6.56; N, 12.01. Found: C,56.48; H, 6.41; N, 12.06.

To a solution of m-nitroaniline (1.0 g, 7.24 mmol) stirred in anhydrousN,N-dimethylformamide (40 mL) at room temperature was added a solutionof a compound of Preparation 5 (2.11 g, 8.69 mmol) in anhydrousN,N-dimethylformamide (10 mL). After 2.5 h, the reaction mixture wasdiluted with H₂O (70 mL) and extracted with ethyl acetate. The combinedorganic extracts were washed with brine, dried (Na₂SO₄), andconcentrated to give a yellow oil. Purification by radial chromatography(silica gel, 10%-75% ethyl acetate/hexanes) provided 1.65 g (76%) of theproduct (1:1 mixture of diastereomers) as an orange solid. ¹H NMR (300MHz, CDCl₃) d 7.47-7.53 (m, 3H), 7.33-7.41 (m, 4H), 7.20-7.25 (app. t,1H, J=8.1 Hz), 6.81-6.85 (dd, 1H, J=8.0 Hz; 2.1 Hz), 5.10 (s, 1H),4.12-4.26 (m, 2H), 1.20-1.25 (t, 3H, J=7.1 Hz); ¹³C NMR (75.5 MHz,CDCl₃) d 171.0, 149.2, 146.5, 136.4, 129.6, 128.9, 128.5, 127.0, 119.1,112.5, 107.2, 62.1, 60.3, 13.9; FD+MS for C₁₆H₁₆N₂O₄=300; Anal. calcd.for C₁₆H₁₆N₂O₄: C, 63.99; H, 5.37; N, 9.33; Found: C, 64.77; H, 5.26; N,9.17.

To a slurry of sodium hydride (0.15 g of a 60% dispersion in mineraloil, 3.86 mmol) stirring in N,N-dimethylformamide (30 mL) at roomtemperature, was added a solution of 6-nitrobenzimidazole (0.60 g, 3.68mmol) in N,N-dimethylformamide (10 mL). After 10 min, a solution ofα-bromophenylacetic acid ethylester in N,N-dimethylformamide (10 mL) wasadded and the solution stirred for 4 h at room temperature, quenchedwith water, and extracted with ethyl acetate. The combined organicextracts were washed with water, brine, dried (Na₂SO₄) and concentrated.Purification by silica gel chromatography (25%-75% ethylacetate/hexanes) gave 0.580 g (50%) of the product (mixture ofdiastereomers) as a yellow oil: ¹H NMR (300 MHz, CDCl₁₃) d 8.72-8.73 (d,1H, J=2.1 Hz), 8.22-8.27 (dd, 1H, J=9.2 Hz; 2.1 Hz), 8.15 (s, 1H),7.44-7.50 (app. t, 3H, J=6.9 Hz), 7.34-7.41 (m, 3H), 6.19 (s, 1H),4.26-4.39 (m, 2H), 1.27-1.33 (t, 3H, J=6.9 Hz); FD+MS forC₁₇H₁₅N₃O₄=325; Anal. calcd. for C₁₇H₁₅N₃O₄: C, 62.76; H, 4.65; N,12,92; Found: C, 62.89; H, 4.92; N, 12.92.

To a solution of a compound of Preparation 50 (0.81 g, 2.73 mmol)stirring in dioxane (30 mL) at room temperature was added LiOH.H₂O (0.57g, 13.6 mmol) and H₂O (15 mL). After 45 min, the mixture wasconcentrated to a volume of approximately 20 mL. The resulting aqueoussolution was diluted with H₂O (75 mL) and extracted with diethyl ether.The aqueous layer was acidified with 1N HCl and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated to give 0.71 g (95%) of the product (1:1mixture of diastereomers) as a yellow solid: ¹H NMR (300 MHz, CDCl₃)δ7.48-7.55 (m, 3H), 7.35-7.43 (m, 4H), 7.21-7.27 (app. t, 1H, J=8.1 Hz),6.81-6.85 (dd, 1H, J=8.2 Hz; 2.0 Hz), 5.16 (s, 1H); FD+MS forC₁₄H₁₂N₂O₄=272; Anal. calcd. for C₁₄H₁₂N₂O₄: C, 61.76; H, 4.44; N,10.29; Found: C, 62.15; H, 4.52; N, 9.63.

To a solution of a compound of Preparation 51 (0.48 g, 1.48 mmol)stirring in dioxane (20 mL) at room temperature was added LiOH.H₂O (0.31g, 7.38 mmol) and H₂O (10 mL). After 45 min, the reaction mixture wasconcentrated to a volume of approximately 15 mL. The resulting aqueoussolution was diluted with H₂O (75 mL) and extracted with diethyl ether.The aqueous layer was acidified with 1N HCl and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated to give 0.450 g (>95%) of the product (1:1mixture of diastereomers) as a light yellow solid: ¹H NMR (300 MHz,DMSO) δ8.63 (s, 1H), 8.56-8.57 (d, 1H, J=2.1 Hz), 8.14-8.20 (dd, 1H,J=9.2 Hz; 2.1 Hz), 7.82-7.86 (d, 1H, J=9.2 Hz), 7.52-7.58 (m, 2H),7.38-7.49 (m, 3H), 6.88 (s, 1H); FD+MS for C₁₅H₁₁N₃O₄=297; Anal. calcd.for C₁₅H₁₁N₃O₄: C, 60.61; H, 3.73; N, 14.14; Found: C, 59.59; H, 4.16;N, 12.78.

To a solution of a compound of Preparation 52 (0.75 g, 2.78 mmol),L-proline methyl ester hydrochloride (0.46 g, 2.78 mmol),1-hydroxybenzotriazole hydrate (0.38 g, 2.78 mmol) andN,N-diisopropylethylamine (1.26 g, 9.72 mmol) in anhydrous1,2-dichlormethane (30 mL) stirring at room temperature, was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.585 g, 3.05 mmol).After 18 h, the reaction mixture was diluted with H₂O (50 mL) extractedwith ethyl acetate. The combined organic extracts were washed with 10%citric acid, sat'd aqueous sodium bicarbonate, water, brine, dried(Na₂SO₄) and concentrated. Purification by radial chromatography (silicagel, 40%-75% ethyl acetate/hexanes) gave 0.56 g (53%) of the product(1:1 mixture of diastereomers) as a yellow solid: ¹H NMR (300 MHz,CDCl₃) δ7.43-7.50 (m, 3H), 7.27-7.43 (m, 4H), 7.13-7.20 (app. t, 1H,J=7.5 Hz), 6.83-6.91 (t, 1H, J=5.8 Hz), 5.14 (s, 1H), 4.52-4.58 (m,0.5H), 4.41-4.47 (m, 0.5H), 3.89-3.97 (m, 1H), 3.71 (s, 1.5H), 3.62 (s,1.5H), 3.23-3.36 (m, 1H), 1.82-2,24 (m, 5H); ¹³C NMR (75.5 MHz, CDCl₃) d172.2, 171.7, 168.7, 168.5, 149.0, 146.9, 146.5, 136.4, 135.9, 129.5,129.4, 129.0, 128.8, 128.5, 128.2, 128.0, 127.8, 119.9, 119.6, 112.2,112.0, 106.5, 106.5, 59.5, 59.4, 59.3, 59.3, 52.2, 52.0, 46.7, 46.7,28.7, 28.6, 24.9, 24.5; FD+MS for C₂₀H₂₁N₃O₅=383; Anal. calcd. forC₂₀H₂₁N₃O₅: C, 62.65; H, 5.52; N, 10.96; Found: C, 61.93; H, 5.62; N,10.46.

To a solution of a compound of Preparation 53 (0.43 g, 1.46 mmol),L-proline methyl ester hydrochloride (0.24 g, 1.46 mmol),1-hydroxybenzotriazole hydrate (0.20 g, 1.46 mmol) andN,N-diisopropylethylamine (0.66 g, 5.10 mmol) stirring in anhydrous1,2-dichlormethane (30 mL) at room temperature was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.60 mmol). After18 h, the reaction mixture was quenched with H₂O(50 mL) and extractedwith ethyl acetate. The combined organic extracts were washed with 10%citric acid, saturated aqueous sodium bicarbonate, H₂O, brine, dried(Na₂SO₄) and concentrated. Purification by radial chromatography (silicagel, 50% ethyl acetate/hexanes to 100% ethyl acetate gradient) gave 0.25g (42%) of the a single diastereomer as a white foam solid: ¹H NMR (300MHz, CDCl₃) d 8.75-8.76 (δ1H, J=2.1 Hz), 8.28-8.32 (dd, 1H, J=8.9 Hz;2.1 Hz), 7.91 (s, 1H), 7.45-7.58 (m, 6H), 6.26 (s, 1H), 4.65-4.70 (m,1H), 3.83-3.92 (m, 1H), 3.78 (s, 3H), 3.30-3.39 (m, 1H), 1.95-2.30 (m,5H); FD+MS for C₂₁H₂₀N₄O₅=408; Anal. calcd. for C₂₁H₂₀N₄O₅: C, 61.76; H.4.94; N, 13.72; Found: C, 61.24; H, 5.16; N, 13.10.

To a slurry of 5% Pd/C (0.07 g) in ethanol (30 mL) was added a solutionof a compound of Preparation 54 (0.15 g, 0.39 mmol) in ethyl acetate (30mL). The mixture was treated with hydrogen gas (32 psi) at roomtemperature for 4 h on a Parr apparatus then carefully filtered throughcelite. The resulting filtrate was evaporated to provide an off-whitesolid foam which was dissolved in N,N-dimethylformamide (30 mL). To thissolution was added a compound of Preparation 4 (0.16 g, 0.41 mmol),1-hydroxybenzotriazole hydrate (0.06 g, 0.41 mmol) and1,3-dicyclohexylcarbodiimide (0.09 g, 0.45 mmol). This solution wasstirred overnight at room temperature and subsequently diluted withwater (50 mL) then extracted with ethyl acetate. The combined organicextracts were washed with water, brine, dried (Na₂SO₄) and evaporated toprovide a tan foam. Purification by radial chromatography (silica gel,50% ethyl acetate/hexanes to 100% ethyl acetate gradient) yielded 0.23 g(82%) of the product (mixture of diastereomers) as an off-white solidfoam. ¹H NMR (300 MHz, CDCl₃) d 8.83-8.91 (m, 1H), 7.44-7.51 (m, 2H),7.20-7.36 (m, 8H), 6.88-7.06 (m, 3H), 6.32-6.38 (app. t, 1H, J=6.9 Hz),5.28 (s, 1H), 5.12-5.19 (m, 1H), 4.88-4.91 (br. s, 1H), 4.48-4.60 (m,3H), 4.17-4.24 (m, 1H), 3.64-3.72 (app. q, 2H, J=8.0 Hz), 3.62 (s, 3H),3.39-3.52 (m, 1H), 3.28-3.39 (m, 1H), 1.81-2.15 (m, 5H), 1.53-1.57 (app.d, 3H, J=7.9 Hz), 1.38 (s, 3H), 1.39 (s, 9H); FD+MS for C₃₉H₄₉N₅O₈=716;Anal. calcd. for C₃₉H₄₉N₅O₈: C, 65.44; H, 6.90; N, 9.78; Found: C,65.23; H, 7.43; N, 10.34.

To a slurry of 5% Pd/C (0.042 g) in ethanol (30 mL) was added a solutionof a compound of Preparation 55 (0.08 g, 0.20 mmol) in ethyl acetate (30mL). The mixture was treated with hydrogen gas (32 psi) at roomtemperature for 4 h (Parr apparatus) then carefully filtered throughcelite. The resulting filtrate was evaporated to provide a white solidfoam which was dissolved in N,N-dimethylformamide (20 mL). To thissolution was added a compound of Preparation 4 (0.08 g, 0.20 mmol),1-hydroxybenzotriazole hydrate (0.03 g, 0.22 mmol) and1,3-dicyclohexylcarbodiimide (0.05 g, 0.22 mmol). This solution wasstirred overnight at room temperature and subsequently diluted withwater (50 mL) then extracted with ethyl acetate. The combined organicextracts were washed with water and brine, dried (Na₂SO₄) andconcentrated. Purification by radial chromatography (silica gel, 75%ethyl acetate/hexanes to 100% ethyl acetate gradient) yielded 0.10 g(66%) of the product (one diastereomer) as an off-white solid foam: ¹HNMR was consistent with structure; FD+MS for C₄₀H₄₈N₆O₈=740.

Example 13

To a solution of a compound of Preparation 56 (0.17 g, 0.24 mol) andanisole (0.03 g, 0.26 mmol) stirring in anhydrous dichloromethane (5 mL)at 0° C. was added trifluoroacetic acid (1 mL). After 4 h, the reactionmixture was quenched carefully with saturated aqueous sodium bicarbonateextracted with ethyl acetate. The combined organic extracts were washedwith sat'd aqueous sodium bicarbonate, water, brine, dried (NaS₂O₄) andevaporated to yield the desired product (1:1 mixture of diastereomers)as an off-white foam: 0.100 g (67%). ¹H NMR was consistent withstructure; FD+MS for C₃₄H₄₁N₅O₆=615; Anal. calcd for C₃₄H₄₁N₅O₆: C,66.32; H, 6.71; N, 11.37; Found: C, 65.83; H, 6.50; N, 6.50.

Example 14

To a solution of a compound of Preparation 57 (0.080 g, 0.11 mmol) andanisole (0.0123 g, 0.114 mmol) stirring in anhydrous dichloromethane (5mL) at 0° C. was added trifluoroacetic acid (1 mL). After 4 h, themixture was quenched carefully with saturated sodium bicarbonate andextracted with ethyl acetate. The combined organic extracts were washedwith saturated aqueous sodium bicarbonate, water, brine, dried (NaS₂O₄)and concentrated to yield foam 0.09 g (95%) of the desired product (onediastereomer) as an off-white solid: ¹H NMR was consistent withstructure; FD+MS for C₃₅H₄₀N₆O₆.2CF₃COOH=640 (M-2CF₃COOH); Anal. calcd.for C₃₉H₄₂N₆O₁₀F₆: C, 53.92; H, 4.87; N, 9.67; Found: C, 51.86; H, 4.74;N, 9.54.

EXAMPLES PART 2A

tert-Butyloxycarbonyl-O-benzyl-D-serine methyl ester

To a solution of t-butyloxycarbonyl-O-benzyl-D-serine (25.0 g, 84.7mmol) stirring in dimethylformamide (500 mL) at room temperature wasadded sodium bicarbonate (14.2 g, 169 mmol) followed by methyl iodide(26.4 mL, 424 mmol). After 18 h, the reaction mixture was concentratedto approximately 100 mL. Ethyl acetate was added and the mixture washedwith aqueous sodium bicarbonate and brine. The organic extract was driedand concentrated to give the desired compound (25 g, 96%) as a lightyellow oil: ¹H NMR (300 MHz, CDCl₃) d 1.45 (s, 9H), 3.70 (m, 1H), 3.75(s, 3H), 3.85 (m, 1H), 4.50 (m, 3H), 7.30 (m, 5H); MS (FD) m/e 310;Anal. calce'd for C₁₆H₂₃NO₅: C, 62.12; H, 7.49; N, 4.53. Found: C,62.31; H, 7.49; N, 4.43.

O-benzyl-D-serine methyl ester

To a solution of tert-butyloxycarbonyl-O-benzyl-D-serine methyl ester(BF8-EZ0-275) (5.0 g, 16 mmol) stirring in dichloromethane (40 mL) andanisole (1 mL) at 0° C. was added trifluoroacetic acid (10 mL). After 4h at room temperature, a saturated aqueous solution of sodiumbicarbonate was added and the resulting mixture extracted with ethylacetate. The combined organic extracts were washed with brine, driedover sodium sufate, and concentrated. The crude product was used in thenext step without further purification.

To a solution of O-benzyl-D-serine methyl ester (the product ofPreparation 1b) (65.4 mmol), boc-a-aminoisobutyric acid (13.2 g, 65.4mmol), 1-hydroxybenzotriazole (8.8 g, 65.4 mmol), andN,N-diisopropylethylamine (22.8 mL, 130.7 mmol) stirring indichloromethane (500 mL) at 0 ° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (12.3 g, 71.9 mmol). After18 h, ethyl acetate and ammonium chloride (saturated aqueous solution)were added and the resulting mixture extracted with aqueous ammoniumchloride, aqueous sodium bicarbonate, and brine. The organic extractswere dried over sodium sulfate and concentrated. Purification by flashchromatography (25% ethyl acetate/hexanes) yielded the desired compound(21.6 g, 83%) as a white solid: ¹H NMR (300 MHz, CDCl₃) d 1.39 (s, 9H),1.48 (s, 6H), 3.62 (dd, J=3.4, 9.1 Hz, 1H), 3.70 (s, 3H), 3.85 (dd,J=3.4, 9.1 Hz, 1H), 4.48 (dd, J=12.5, 22.7 Hz, 2H), 4.75 (m, 1H), 4.92(s, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.35 (m, 5H); MS (FD) m/e 395; Anal.calc'd for C₂₀H₃₀N₂O₆: C, 60.90; H, 7.67; N, 7.10. Found: C, 61.02; H,7.78; N, 7.10.

To a solution of the product of Preparation 1c (5.30 g, 13.4) stirringin dioxane (100 mL)/water (50 mL) at room temperature was added lithiumhydroxide (2.80 g, 67.3 mmol). After 18 h, water was added and thesolution concentrated. The resulting mixture was extracted with diethylether. Brine was added to the aqueous layer and the pH adjusted to 3.5with 1N HCl. The resulting mixture was extracted with ethyl acetate andthe combined organic extracts dried over sodium sulfate thenconcentrated to yield the title compound (4.40 g, 86%) as a white foam:¹H NMR (300 MHz, CDCl₃) d 1.39 (s, 9H), 1.45 (s, 3H), 1.47 (s, 3H), 3.68(m, 1H), 3.95 (m, 1H), 4.54 (s, 2H), 4.70 (m, 1H), 5.51 (bs, 1H), 7.18(d, J=9.1 Hz, 1H), 7.25 (m, 5H), 9.90 (bs, 1H); MS (FD) m/e 381; Anal.calc'd for C₁₉H₂₈N₂ _(O) ₆: C, 59.99; H, 7.42; N, 7.36. Found: C, 59.74;H, 7.26; N, 7.30.

A solution of sodium ethoxide was generated by the addition of sodiummetal (52.89 grams, 2.3007 mol) over 3 hours to ethanol (1500 mL). Tothe sodium ethoxide solution at ambient temperature was added a solutionof diethylacetamidomalonate (499.75 grams, 2.3007 mol) dissolved inethanol (225 mL). The reaction mixture was stirred for 1.5 hours atambient temperature. 1-bromo-3-phenylpropane (458.07 grams, 2.3007 mol)was added over 15 minutes and the reaction mixture was refluxed untilcomplete as determined by hplc (16 hours). The reaction mixture wasconcentrated to dryness and the residue partitioned between ethylacetate (1×1500 mL and 2×500 mL) and water (1500 mL). The ethyl acetatelayers were combined, washed with saturated sodium chloride solution(4×500 mL), dried using sodium sulfate, and concentrated to give 752.1grams (98%) of the desired compound as a light yellow solid. A 1.0 gramsample was recrystallized from hexane:ethyl acetate (19:1, v:v) to givea mp 84-86° C. ¹H nmr (CDCl₃): δ1.18-1.23 (t, 6H), 1.37-1.50 (m, 2H),2.02 (s, 3H), 2.34-2.41 (m, 2H), 2.58-2.62 (t, 2H), 4.16-4.24 (q, 4H),6.76 (s, broad, 1H), 7.11-7.28 (m, 5H). ¹³C nmr (CDCl₃): δ13.95, 23.03,25.67, 31.85, 35.45, 62.46, 66.49, 125.40, 125.90, 128.27, 128.35,141.77, 168.11, 168.94. MS (FIA) m/z 336.3 ([M+H]⁺). IR (KBr, cm⁻¹)1645.98 (amide), 1744.76 (C=O). Anal. Calcd. for C₁₈H₂₅NO₅: C, 64.46; H,7.51; N, 4.17. Found: C, 64.60; H, 7.37; N, 4.39.

(DL)-N-Acetyl-2-amino-5-phenylpentanoic Acid

A slurry consisting of the product of Preparation 1e (249.15 grams,0.7428 mol) and 2.5 N sodium hydroxide solution was heated at 100° C.for three hours. The reaction mixture was cooled to 30° C. and the pHadjusted to 5.0 using concentrated hydrochloric acid. The solution washeated to 100° C. and the pH was held at 5.0 using concentratedhydrochloric acid as needed until the reaction was complete asdetermined by hplc. The solution was filtered while hot throughdiatomaceous earth. The filtrate was cooled to 5-10° C. and the pHadjusted to 1.0 using concentrated hydrochloric acid. The resultingslurry was stirred for 1 hour at 5° C., filtered, and dried in vacuum at50° C. to give 160.34 grams (92%) of(DL)-N-acetyl-2-amino-5-phenylpentanoic acid as a white powder, mp145-148° C. ¹H nmr (DMSO-d₆): δ1.60-1.71 (m, 4H), 1.86 (s, 3H),2.56-2.59 (m, 2H), 4.19-4.23 (m, 1H), 7.16-7.30 (m, 5H), 8.14 (d, 1H).¹³ C nmr (DMSO-d₆): δ23.17, 28.25, 31.55, 35.51, 52.55, 126.60, 129.14,142.64, 170.25, 174.65. MS (FIA) m/z 236.2 (M⁺). IR (KBr, cm³¹ ¹)1609.17 (amide), 1741.12 (C═O). Anal. Calcd. for C₁₃H₁₇NO₃: C, 66.36; H,7.28; N, 5.95. Found: C, 66.41; H, 7.15; N, 5.96.

(D)-N-Acetyl-2-amino-5-phenylpentanoic Acid

A solution consisting of (DL)-N-acetyl-2-amino-5-phenylpentanoic acid(438.0 grams, 1.862 mol), cobalt chloride (1.10 grams), 2N potassiumhydroxide solution (931 mL, 1.862 mol), and water (8000 mL) was adjustedto a pH of 8.0 by the addition of 2N potassium hydroxide solution. Tothe reaction mixture was added Acylase I (aspergillus melleus, 39.42grams) and vigorously stirred for 24 hours at 40° C. while maintaining apH of 8.0 by addition of 2N potassium hydroxide. The resulting slurrywas filtered. The filtrate was adjusted to a pH of 2.0 giving a thickslurry. The product was isolated by filtration, washed with hexane (2000mL) and dried in vacuum at 50° C. to give 188.52 grams (43%) of(D)-N-acetyl-2-amino-5phenylpentanoic acid. ¹H nmr ( DMSO-d₆):δ1.59-1.74 (m, 4H), 1.86 (s, 3H), 2.57-2.60 (m, 2H), 4.22-4.26 (m, 1H),7.16-7.30 (m, 5H), 8.02 (d, 1H), 12.39 (s, broad, 1H). ¹³C mnr (DMSO-d₆): δ23.18, 28.13, 31.66, 35.54, 52.58, 126.56, 129.10, 142.67,170.12, 174.48. MS (FIA) m/z 236.1 (M⁺). IR (KBr, cm⁻¹) 1625.08 (amide),1700.24 (C═O). Anal. Calcd. for C₁₃H₁₇NO₃: C, 66.36; H, 7.28; N. 5.95.Found: C, 66.49; H, 7.00; N, 6.03.

(D)-2-Amino-5-phenylpentanoic Acid, Ethyl Ester Hydrochloride

A solution consisting of (D)-N-acetyl-2-amino-5-phenylpentanoic acid(188.8 grams, 0.8024 mol), ethanol (535 mL), and concentratedhydrochloric acid (268 mL, 3.21 mol) was warmed to 85 ° C. and monitoredby hplc. The reaction was determined to be incomplete by hplc at 14.5hours and additional concentrated hydrochloric acid (50 mL) was added.The reaction was determined to be complete by hplc after 22.5 hours.Water was azeotropically distilled from the reaction by continuousaddition and distillation of 8000 mL of ethanol. The ethanol wasazeotropically distilled from the reaction by the continuous additionand distillation of ethyl acetate (2000 mL). Upon cooling the solutionto 0° C. the product crystallized. The solution containing the productwas stirred for 1 hour at 0° C., filtered, and the cake dried in vacuumat 40° C. to give 199.0 grams (96%) of 2-amino-5-phenylpentanoic acid,ethyl ester hydrochloride, mp 117-121° C. ¹H nmr ( DMSO-d₆): δ1.15-1.21(t, 3H), 1.50-1.89 (m, 4H), 2.48-2.67 (m, 2H), 3.92-3.98 (t, 1H),4.08-4.25 (m, 2H), 7.12-7.29 (m, 5H), 8.76 (s, broad, 3H). ¹³C nmr(DMSO-d₆): δ13.90, 25.97, 29.52, 34.41, 51.71, 61.56, 124.91, 125.81,128.24, 141.27, 169.35. MS (FIA) m/z 222.3 (M⁺). IR (KBr, cm⁻¹) 1741.14(C═O). [α]²⁰ _(D)=−11.17(c=30.62 mg /3 mL, MeOH). Anal. Calcd. forC₁₃H₂₀NO₂Cl: C, 60.58; H, 7.82; N, 5.43. Found: C, 60.45; H, 7.67; N,5.55.

A slurry consisting of N-t-BOC-α-aminoisobutyric acid (90.64 grams,0.446 mol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (75.90 grams, 0.425mol), N-methyl morpholine (88.13 grams, 0.871 mol), and diethyl ether(1000 mL) was stirred at ambient temperature until complete asdetermined by hplc (3 hours). The D-2-amino-5-phenylpentanoic acid,ethyl ester hydrochloride (109.55 grams, 0.425 mol) was added and thereaction mixture stirred for 16 hours at ambient temperature. Thereaction mixture was partitioned between 10% citric acid solution (1000mL) and ethyl acetate (3×500 mL) . The organic phase was washed with 10%citric acid solution (3×500 mL), saturated sodium bicarbonate solution(3×500 mL), water (1×500 mL), dried using sodium sulfate, andconcentrated to dryness. The residue was recrystallized from hexane(3000 mL) to give 155.11 grams of the desired compound: mp 97-99° C. ¹Hnmr (CDCl₃): δ1.25-1.28 (t, 3H), 1.43 (s, 9H), 1.48 (s, 3H), 1.50 (s,3H), 1.70-1.73 (m, 3H), 1.87-1.93 (m, 1H), 2.62-2.67 (m, 2H), 4.16-4.21(m, 2H), 4.57-4.62 (m, 1H), 4.95 (s, 1H), 6.96 (s, broad, 1H), 7.16-7.19(m, 3H), 7.26-7.33 (m, 2H). ¹³C nmr (CDCl₃): δ14.53, 26.32, 27.17,28.67, 32.47, 35.73, 52.54, 57.17, 61.62, 126.21, 128.69, 128.79,142.12, 154.99, 172.81, 174.69. MS (FIA) m/z 407.5 ([M+H]⁺). IR (KBr,cm³¹ ¹) 1652.75, 1685.52 (amides), 1741.73 (C═O). [α]²⁰ _(D)=7.83(c=10.22 mg /1 mL, MeOH). UV (0.1% trifluoroacetic acid inwater:acetonitrile) λ_(max)215.6 nm. Anal. Calcd. for C₂₂H₃₄N₂O₅: C,65.00; H, 8.43; N, 6.89. Found: C, 65.23; H, 8.34; N, 6.94.

A solution consisting of the product of Preparation 1i (152.53 grams,0.3752 mol) and tetrahydrofuran (884 mL) was cooled to 5° C. A solutionconsisting of lithium hydroxide (26.96 grams, 1.126 mol) and water (1419mL) was added to the reaction dropwise over 10 minutes maintaining atemperature of 5-10° C. Ethanol (183 mL) was added and the reactionstirred at 5-10° C. until complete as determined by hplc (2 hours). ThepH of the reaction mixture was adjusted to 2.0 using 6 N hydrochloricacid solution while maintaining 5-10° C. The product was extracted fromsolution with ethyl acetate (3×500 mL). The ethyl acetate extracts werecombined, dried using sodium sulfate, and concentrated to dryness togive 141.51 grams (100%) of The desired compound: ¹H nmr ( DMSO-d₆):δ1.32-1.37 (m, 15H), 1.57-1.75 (m, 4H), 2.51-2.58 (m, 2H), 4.23-4.27 (m,1H), 6.85 (s, broad, 1H), 7.15-7.28 (m, 5H), 7.42 (d, 1H), 12.5 (s,broad, 1H). ¹³C nmr ( DMSO-d₆): δ26.31, 27.85, 29.00, 31.86, 35.60,52.53, 56.60, 78.95, 126.52, 129.05, 129.10, 142.69, 155.06, 174.40,175.17. MS (FIA) m/z 379.5 ([M+H]⁺). IR (KBr, cm⁻¹) 1641.98, 1692.22(amides), 1719.72 (C═O). [α]²⁰ _(D)=−5.73 (c=10.48 mg / 1 mL, MeOH).Anal. Calcd. for C₂₀H₃₀N₂O₅: C, 63.47; H, 7.99; N, 7.40. Found: C,63.25; H, 7.84; N. 7.46.

N-Methyl morpholine (4.79 mL, 2 eq, 47.3 mm) was added to a stirredslurry of N-Boc-a-aminoisobutyric acid (4.43 g, 21.7 mm, 1 eq) and 3.89g (21.7 mm, 1.0 eq) of 2-chloro-(4,6)-dimethoxy-1,3,5-triazine (CDMT) in100 mL of diethyl ether. After stirring the reaction mixture at ambienttemperature for 1.5 hours, D-tryptophan ester hydrochloride was added.After stirring overnight, the reaction mixture was quenched by theaddition of 150 mL of 10% aqueous citric acid solution. The layers wereseparated and the ether layer was washed with 50 mL of saturated sodiumbicarbonate solution and 50 mL of water. Lithium hydroxide (2.43 g, 5eq) was dissolved in 100 ml of water and the solution was added to thediethyl ether solution and stirred vigorously for 4 hours at roomtemperature. The layers were separated and the pH of the aqueous layerswas adjusted to 5.6 with 1M HCl. The pH was then adjusted to 3.95 with10% citric acid solution and the aqueous layer was extracted with 100 mLof ethyl acetate. The ethyl acetate layers were washed with brine, driedover magnesium sulfate and filtered. The volatiles were removed undervacuum to give 82% yield of the desired product as a white foam. 1H-NMRconsistent with structure.

To a solution of 4-methoxyphenylacetic acid (98 g, 590 mmol) in absoluteethanol (300 mL) was added of p-toluenesulfonic acid (20 g, 105 mmol).The reaction mixture was heated to reflux and maintained at thattemperature for 5 h then cooled to room temperature and concentrated todryness. The resulting oil was purified by flash chromatography (silicagel, 20% ethyl acetate/hexanes) to give 102 g (89%) of the desiredproduct as a colorless oil: ¹H-NMR (d, DMSO) 1.17 (t, J=8.7 Hz, 3H),3.56 (S, 2H), 3.73 (s, 3H), 4.05 (q, J=7.2 Hz, 2H), 6.87 (d, J=8.7 Hz,2H), 7.17 (d, 8.7 Hz, 2H); MS (ion spray) 195.3 (M+1); Anal. Calc'd forC₁₁H₁₄O₃: C, 68.02; H, 7.27. Found: C, 67.95, 7.17.

To a solution of the product of Preparation 2A (40 g, 200 mmol) incarbon tetrachloride (500 ml) was added N-bromosuccinimide (37 g, 206mmol) and hydrobromic acid (4 drops of 48% aqueous solution). Theresulting mixture was heated to reflux and maintained at thattemperature for 5 h then cooled to room temperature, filtered, andconcentrated. The resulting oil was purified by flash chromatography(silica gel, chloroform) to give 51.1 g (94%) of the desired product asa colorless oil: ¹H-NMR (d, DMSO) 1.19 (t, J=8.4 Hz, 3H), 3.77 (s, 3H),4.18 (m, 2H), 5.88 (s, 1H), 6.95 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz,2H); MS (FD) 272, 274 (M+); Anal. Calc'd for C₁₁H₁₃BrO₃: C, 48.37; H,4.80. Found: C, 48.52, 4.77.

To a solution of the product of Preparation 2B (49.5 g, 181 mmol)stirring in dimethylformamide (500 mL) at room temperature was added4-nitroimidazole (20.5 g, 181 mmol) and potassium carbonate (75 g, 543mmol). After 16 h, the reaction was filtered and concentrated. Theresulting oil was partitioned between ethyl acetate and water andextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated. Theresulting oil was purified by flash chromatography (silica gel, 30-70%ethyl acetates/hexanes gradient) to yield 33.6 g (61%) of the desiredproduct as an orange oil that solidifies upon standing: ¹H-NMR (d, DMSO)1.17 (t, J=7.2 Hz, 3H), 3.78 (s, 3H), 4.25 (q, J=7.2 Hz, 2H), 6.57 (s,1H), 7.02 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H), 7.92 (s, 1H), 8.38(s, 1H); MS (ion spray) 306 (M+1); Anal. Calc'd for C₁₄H₁₅N₃O₅: C,55.08; H, 4.95; N, 13.76. Found: C, 54.93; H, 4.89; N. 13.82.

To a slurry of 10% palladium on carbon (6.0 g) in tetrahydrofuran (30mL) was added a slurry of the product of Preparation 3 (8.4 g, 27.5mmol) in tetrahydrofuran (30 mL). The reaction mixture placed under ahydrogen atmosphere (40 mm Hg) using a Parr apparatus until thereduction was complete then filtered through celite. To the resultingsolution stirring at room temperature was added the product ofPreparation 1d (10.5 g, 27.5 mmol), 1-hydroxybenzotriazole (4.1 g, 30.3mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (6.3 g, 30.3mmol) . After 16 h, the reaction mixture was concentrated and theresulting oil was slurried in ethyl acetate and filtered. The solutionwas diluted with water and then extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The resultant crude material waspurified by flash chromatography (silica gel, 3% methanol/chloroform) togive 14.4 g (83%) of the desired product as a tan foam: ¹H-NMR (d, DMSO)1.78 (t, J=7.2 Hz, 3H), 1.27-1.32 (m, 15H), 3.60 (m, 1H), 3.67 (m, 1H),3.76 (s, 3H), 4.20 (d, J=7.2 Hz, 2H), 4.44 (d, J=3.0 Hz, 2H), 4.57 (m,1H), 6.35 (s, 1H), 6.97 (d, J=7.2 Hz, 2H), 7.20-7.35 (m, 10H), 7.40 (m,1H) , 7.52 (s, 1H); MS (ion spray) 638 (M+1); Anal. Calc'd forC₃₃H₄₃N₅O₈: C, 62.15; H, 6.80; N, 10.98. Found: C, 62.41; H, 6.85; N,11.09.

To a solution of the product of Preparation 4 (14.4 g, 23 mmol) stirringin dioxane (150 mL) at room temperature was added a solution of oflithium hydroxide (0.65 g, 27.6 mmol) in water (75 mL). After 20 min,the reaction mixture was acidified to pH=2.9 with 1 N hydrochloric acid.To the resulting solution was added water and ethyl acetate the mixturewas extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried over sodium sulfate and concentrated to yield13.0 g (93%) of the desired product as a yellow foam: ¹H NMR (d, DMSO)1.25-1.40 (m, 15H), 3.65-3.70 (m, 2H), 3.76 (s, 3H), 4.44 (d, J=3.4 Hz,2H), 4.57 (m, 1H), 6.20 (s, 1H), 6.97 (d, J=3.4 Hz, 2H), 7.15-7.35 (m,10H), 7.42 (m, 1H), 7.53 (s, 1H), 10.2 (s, 1H); MS (ion spray) 610.7(M+1); Anal. Calc'd for C₃₁H₃₉N₅O₈: C, 61.07; H, 6.45; H, 11.49. Found:C, 60.90; H, 6.43; N, 11.32.

To a solution of the product of Preparation 5 (8.0 g, 13.0 mmol)stirring in dimethylformamide (150 mL) at room temperature was added4-methylpiperidine (1.6 mL, 13.0 mmol), 1-hydroxybenzotriazole (2.0 g,14.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.0 g,14.3 mmol). After 16h, the reaction mixture was filtered andconcentrated. The resulting material was partitioned between ethylacetate and water and extracted with ethyl acetate. The combined organicextracts were washed with brine, dried over sodium sulfate, filtered andconcentrated to dryness. The resulting crude material was purified byflash chromatography (silica gel, 3% methanol/chloroform) to yield 7.65g (85%) of the desired product as a yellow foam: ¹H-NMR (d, DMSO) 0.2(m, 1H), 0.50 (d, J=6.0 Hz, 1.5 H), 0.80 (d, J=6.0 Hz, 1.5 H), 1.05 (m,1H), 1.22-1.45 (m, 15H), 1.50-1.65 (m, 4H), 2.65 (m, 1H), 3.00 (m, 1H),3.55 (m, 1H), 3.65 (m, 1H), 3.75 (s, 3H), 4.37 (m, 1H), 4.40-4.50 (m,2H), 4.60 (m, 1H), 6.62 (d, J=13 Hz, 1H), 6.98 (t, J=9.4 Hz, 2H),7.10-7.45 (m, 11H), 10.15 (br s, 1H); MS (ion spray) 691.3 (M+1); Anal.Calc'd for C₃₇H₅₀N₆O₇.0.6H₂O: C, 63.34; H, 7.35; N, 11.98. Found. C,63.25; H, 7.03; 11.87.

Examples 1 and 2

To a solution of the product of Preparation 6 (7.26 g, 10.5 mmol)stirring in dichloromethane (25 mL) at room temperature was addedtrifluoroacetic acid (10 mL). After 4 h, the reaction mixture was pouredinto a saturated solution of sodium bicarbonate extracted withchloroform. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated to yield 6.12 g (99%) ofthe free base as a tan foam. The diastereomeric material (3.0 g) waschromatographed on an 8×15 cm Prochrom column packed with KromosilCHI-DMP chiral phase using an eluent mixture of 3A alcohol (13% by v),dimethylethylamine (0.2% by v) in heptane at a flow rate of 250 mL/minto provide the individual diastereomers in pure form:

Example 1. Isomer 1 To a solution of the purified isomer in ethylacetate was added a saturated solution of hydrochloric acid in diethylether. The resulting slurry was concentrated to dryness to yield 1.1 g(37%) of the desired product as a white solid: ¹H NMR (d, DMSO) 0.50 (d,J=6.0 Hz, 1.5 H), 0.80 (d, J=6.0 Hz, 1.5 H), 1.16 (m, 1H), 1.35 (m, 1H),1.50-1.70 (m, 8H), 2.60-2.70 (m, 2H), 3.03 (m, 1H), 3.65-3.80 (m, 6H),4.40 (m, 1H), 4.53 (s, 2H), 4.75 (m, 1H), 6.90-7.08 (m, 3H), 7.25-7.45(m, 9H), 8.20-8.40 (m, 4H), 8.61 (d, J=7.5 Hz, 1H), 11.15 (br s, 1H);t_(R)=7.93 min; MS (ion spray) 591.6 (M+1); Anal. Calc'd forC₃₂H₄₂N₆O₅.2HCl: C, 57.92; H, 6.69; N, 12.66. Found: C, 57.72; H, 6.47;N, 12.42.

Example 2. Isomer 2 To a solution of the purified isomer in ethylacetate was added a saturated solution of hydrochloric acid in diethylether. The resulting slurry was concentrated to yield 0.98 g (33%) ofthe desired product as a white solid: ¹H NMR (d, DMSO) 0.50 (d, J=6.0Hz, 1.5 H), 0.80 (d, J=6.0 Hz, 1.5 H), 1.16 (m, 1H), 1.35 (m, 1H),1.50-1.70 (m, 8H), 2.60-2.70 (m, 2H), 3.03 (m, 1H), 3.65-3.80 (m, 6H),4.40 (m, 1H), 4.53 (s, 2H), 4.75 (m, 1H), 6.90-7.08 (m, 3H), 7.25-7.45(m, 9H), 8.20-8.40 (m, 4H), 8.61 (d, J=7.5 Hz, 1H), 11.15 (br s, 1H);t_(R)=11.78 min; MS (ion spray) 591.6 (M+1); Anal. Calc'd forC₃₂H₄₂N₆O₅.2.2HCl: C, 57.29; H, 6.64; N, 12.53. Found: C, 57.23; H,6.29; N, 12.57.

Reaction of the product of Preparation 5 (0.6 g, 1.0 mmol),4-(4-fluorobenzoyl)piperidine hydrochloride (0.24 g, 1.0 mmol),triethylamine (0.15 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.16 g, 1.1mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (40 mL) as described in Preparation 6 gave0.58 g (73%) of the desired product as a tan foam: ¹H-NMR (d, DMSO)1.20-1.40 (m, 18H), 1.40-1.90 (m, 3H), 2.83 (m, 1H), 3.55-3.73 (m, 3H),3.75 (s, 3H), 3.85 (m, 1H), 4.45 (d, J=3.8 Hz, 2H), 4.60 (m, 1H), 6.65(d, J=10.93 Hz, 1H), 6.95-7.05 (m, 2H), 7.10-7.20 (m, 2H), 7.20-7.50 (m,11H), 8.00-8.10 (m, 2H), 10.15 (br s, 1H); MS (FD) 798.7 (M+); Anal.Calcl'd for C₄₃H₅₁FN₆O₈: C, 64.65; H, 6.43; N, 10.53. Found: C, 64.38;H, 6.48; N, 10.61.

Examples 3 and 4

Reaction of the product of Preparation 7 (0.53 g, 0.66 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.34 g (74%) of the desired mixture of diastereomers as atan foam. This material (0.11 g) was purified by HPLC (8×15 cm Prochromcolumn packed with Kromosil CHI-DMP chiral phase, eluent mixture of 3Aalcohol and dimethylethylamine in heptane) to provide the individualdiastereomers which were converted to their repsective hydrochloridesalts as desribed in Example 1.

Example 3. Isomer 1. ¹H-NMR (d, DMSO) 1.15-1.20 (m, 6H), 1.20-1.60 (m,3H), 1.70 (m, 1H), 2.90 (m, 1H), 3.55-3.70 (m, 4H), 3.75 (s, 3H), 3.85(m, 1H), 4.40 (m, 1H), 4.40-4.55 (m, 2H), 4.60 (m, 1H), 6.65 (d, J=11Hz, 1H), 7.00-7.05 (m 2H), 7.20 (m, 1H), 7.20-7.40 (m, 13H), 8.00-8.10(m, 2H), 10.40 (br s, 1H); t_(R)=6.4 min; MS (ion spray) 699.7 (M+1);Anal. Calc'd for C₃₈H₄₃FN₆O₆: C, 65.31; H, 6.20; N, 12.03. Found: C,65.08; H, 6.18; N, 11.87.

Example 4. Isomer 2 ¹H-NMR (d, DMSO) 1.15-1.20 (m, 6H), 1.20-1.60 (m,3H), 1.70 (m, 1H), 2.90 (m, 1H), 3.55-3.70 (m, 4H), 3.75 (s, 3H), 3.85(m, 1H), 4.40 (m, 1H), 4.40-4.55 (m, 2H), 4.60 (m, 1H), 6.65 (d, J=11Hz, 1H), 7.00-7.05 (m 2H), 7.20 (m, 1H), 7.20-7.40 (m, 13H), 8.00-8.10(m, 2H), 10.40 (br s, 1H); t_(R)=8.0 min; MS (high res) calc'd forC₃₈H₄₄FN₆O₆: 699.3306. Found: 699.3313.

Reaction of the product of Preparation 7 (1.0 g, 1.7 mmol), piperidine(0.17 mL, 1.7 mmol), 1-hydroxybenzotriazole (0.25 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol), anddimethylformamide (15 mL) as desribed in Preparation 6 gave 0.7 g (60%)of the desired product as a tan foam: ¹H-NMR (d, DMSO) 0.97 (m, 1H),1.25-1.40 (m, 15H), 1.40-1.55 (m, 7H), 3.30-3.45 (m, 2H), 3.60 (m, 1H),3.67 (m, 1H), 3.75 (s, 3H), 4.45 (d, J=3.4 Hz, 2H), 4.57 (m, 1H), 6.62(s, 1H), 6.98 (d, J=8.7 Hz, 2H), 7.13 (m, 1H), 7.25-7.45 (m, 10H), 10.15(br s, 1H); MS (ion spray) 677.5 (M+1); Anal. Calc'd for C₃₆H₄₈N₆O₇: C,63.89; H, 7.15; N, 12.42. Found: C, 63.97; H, 6.99; N, 12.44.

Example 5

Reaction of the product of Preparation 8 (0.68 g, 1.0 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.6 g (93%) of the desired product as a white solid:¹H-NMR (d, DMSO) 0.95 (m, 1H), 1.30-1.60 (m, 11H), 3.20-3.40 (m, 3H),3.60-3.75 (m, 3H), 3.78 (s, 3H), 4.50-4.55 (m, 2H), 4.75 (m, 1H), 6.80(s, 1H), 7.05 (d, J=9.0 Hz, 2H), 7.25-7.35 (m, 7H), 7.37 (d, J=8.7 Hz,2H), 8.10 (m, 1H), 8.20-8.30 (m, 3H), 8.58 (d, J=7.6 Hz, 1H), 11.00 (brs, 1H); MS (ion spray) 577.4 (M+1); Anal. Calc'd for C₃₁H₄₀N₆O₅.2.2HCl:C, 56.68; H, 6.48; N, 12.79. Found: C, 56.70; H, 6.64; N, 12.37.

Reaction of the product of Preparation 5 (1.42 g, 2.3 mmol), d-prolinemethyl ester (0.3 g, 2.3 mmol), 1-hydroxybenzotriazole (0.35 g, 2.5mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.53 g, 2.5mmol) in tetrahydrofuran (15 mL) as described in Preparation 6 gave 0.99g (60%) of the desired product as a white foam: ¹H-NMR (d, DMSO)1.25-1.40 (m, 18H), 1.75-1.90 (m, 2H), 2.40 (m, 1H), 3.30 (m, 1H),3.60-3.80 (m, 7H), 4.40 (m, 1H), 4.45-4.50 (m, 2H), 4.57 (m, 1H), 6.50(m, 1H), 6.95-7.05 (m, 2H), 7.10-7.40 (m, 11H), 10.20 (br s, 1H); MS(ion spray) 721.3 (M+1); Anal. Calc'd for C₃₇H₄₈N₆O₉: C, 61.65; H, 6.71;N, 11.66. Found: C, 61.42; H, 6.43; N, 11.65.

Example 6

Reaction of the product of preparation 9 (0.87 g, 1.2 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.58 g (70%) of the desired product: ¹H-NMR (d, DMSO)1.40-1.60 (m, 6H), 1.75-1.95 (m, 3H), 2.20 (m, 1H), 2.95 (m, 1H),3.60-3.80 (m, 9H), 4.40 (m, 1H), 4.50-4.55 (m, 2H), 4.75 (m, 1H), 6.70(s, 1H), 7.00 (t, J=8.7 Hz, 2H), 7.40-7.45 (m, 9H), 8.05 (m, 1H),8.20-8.30 (m, 3H), 8.55 (m, 1H), 10.95 (m, 1H); MS (ion spray) 621.5(M+1); Anal. Calc'd for C₃₂H₄₀N₆O₇.2.3HCl: C, 54.55; H, 6.05; N, 11.93.Found: C, 54.46; H, 5.81; N, 11.79.

To a suspension of 5% palladium on carbon (1.75 g) and tetrahydrofuran(120 mL) was added the product of Preparation 3 (3.51 g, 11.5 mmol). Thereaction mixture was placed under a hydrogen atmosphere (40 mm Hg) on aParr apparatus for 2 h then filtered through celite. The filtrate wassubsequently added to a solution of the product of Preparation 1j (4.33g, 11.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.60 g,12.6 mmol) and 1-hydroxybenzotriazole (1.72 g, 12.6 mmol) stirring intetrahydrofuran (50 mL) at 0° C. After 16 h at room temperature, thereaction mixture was concentrated. The resulting residue was dissolvedin ethyl acetate, filtered and the resulting filtrate concentrated. Thecrude residue was purified by flash chromatography (silica gel, 90%ethyl acete/hexanes to 10% methanol/ethyl acetate gradient) to give 4.5g (62 %) the desired product as a light orange foam: ¹H NMR consistentwith structure; MS (IS) m/e 636 (M+1). Anal. (C₃₄H₄₅N₅O₇) C, H, N.

To a solution of the product of Preparation 10 (1.01 g, 1.59 mmol)stirring in tetrahydrofuran (30 mL) and water (15 mL) at roomtemperature was added lithium hydroxide (0.26 g, 6.30 mmol). After 25min, the reaction mixture was concentrated and the resulting residue wasdiluted with water and extracted with diethyl ether. The aqueousextracts were acidified to pH 2-3 with 1N hydrochloric acid and thenextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried with sodium sulfate and concentrated to provide 0.96 g(99%) of the desired compound as a light tan foam that was used withoutfurther purification: ¹H NMR consistent with structure; MS (IS) m/e 608(M+1). Anal. (C₃₂H₄₁N₅O₇) C: calcd, 63.25; found, 62.68, H, N.

To a solution of the product of Preparation 11 (0.93 g, 1.53 mmol)stirring in dichloromethane (25 mL) at room temperature was addedN-methylmorpholine (0.20 mL, 1.83 mmol) and of 2-chloro-(4,6)-dimethoxy-1,3,5-triazine (0.35 g, 1.99 mmol). After 1 h,4-methylpiperidine (0.20 mL, 1.68 mmol) was added and the resultingmixture was stirred room temperature for 2 h at which time2-chloro-(4,6)-dimethoxy-1,3,5-triazine (0.10 g, 0.70 mmol) was added.After 1 h, the reaction mixture was concentrated and the resultingresidue purified by flash chromatography (silica gel, ethylacetate/methanol gradient) to give the desired compound as a lightyellow solid foam (0.875 g, 83%): ¹H NMR consistent with structure; MS(IS) m/e 689 (M+1). Anal. (C₃₈H₅₂N₆O₆) C, H, N.

Example 7

To a solution of the product of Preparation 12 (0.77 g, 1.12 mmol) andanisole (0.13 mL, 1.13 mmol) stirring in dichloromethane (20 mL) at 0 C.was added trifluoroacetic acid. After 3-4 h, the reaction mixture waswarmed to room temperature and then quenched by pouring over coldsaturated aqueous sodium bicarbonate. The organic layer was collectedand the aqueous layer was extracted twice with dichloromethane. Thecombined organic extracts were washed with aqueous sodium bicarbonate,water, brine, then dried over sodium sulfate and concentrated. Theresulting material was purified by flash chromatography (silica gel, 5%methanol/95% ethyl acetate) gradient to 5% triethylamine/10%methanol/85% ethyl acetate) to provide 0.63 g (95%) of the desiredmixture of diastereomers as an off-white solid foam. The mixture (190mg) was resolved by chiral HPLC [Kromasil packing material, 15% 3Aalcohol/85% heptane (w/0.2% dimethylamine)] to provide the two desireddiastereomers. To a solution of diastereomer 2 (65 mg) (retentiontime=9.00 min) stirring in ethyl acetate (5 mL) was added saturatedsolution of hydrochloric acid in diethyl ether. The resulting whiteprecipitate was collected by vacuum filtration and rinsed with diethylether to provide the desired compound (60 mg) as a white amorphoussolid: ¹H NMR consistent with structure; MS (IS) m/e 589 (M+1). Anal.(C₃₃H₄₄N₆O₄.2HCl) C, H, N.

To a solution of Preparation 3 (3.00 g, 9.84 mmol) stirring intetrahydrofuran (10 mL) and ethanol (5 mL) was added to sodium hydroxide(20 mL of a 5 N aqueous solution). The resulting mixture was stirred atambient temperature until hydrolysis was complete and subsequentlyacidified to pH 2.0 with aqueous hydrochloric acid. The reaction mixturewas extracted with ethyl acetate, dried over sodium sulfate, andconcentrated. The resulting carboxylic acid was combined withpyrrolidine (0.710 g, 10 mmol), 1-hydroxybenzotriazole hydrate (1.35 g,10 mmol) and 1,3-dicyclohexylcarbodiimide (2.06 g, 10.0 mmol) stirringin tetrahydrofuran (100 mL) at room temperature. After 18 h, the mixturewas concentrated, the residue slurried in ethyl acetate then filteredand concentrated. Purification by flash chromatography (silica gel,chloroform/methanol) provided afford 2.74 g (84%) of the desiredproduct: MS: (M+H)⁺ 331.2; ¹H NMR (300 MHz, DMSO-d₆) δ8.19 (d, 1H,J=1.51 Hz), 7.80(d, 1H, J=1.51 Hz), 7.45 (d, 2H, J=8.67 Hz),7.02(d, 2H,J=8.67 Hz), 6.58 (s, 1H), 3.77 (s, 3H),3.75-3.60 (m, 1H) 3.45-3.30 (m,2H), 2.90-2.75 (m, 1H)1.95-1.60 (m, 4H); Anal. Calcd. for C₁₆H₁₈N₄O₄: C,58.18; H, 5.49;N, 16.96. Found: C, 58.44; H, 5.45; N, 16.87.

The product of Preparation 13 (1.13 g, 3.42 mmol) was added to a mixtureof 10% palladium/carbon (0.65 g) and palladium/black (0.15 g) intetrahydrofuran (40 mL) and the mixture shaken under hydrogen (38 psi)in a Parr apparatus. After reduction was complete, the reaction mixturewas filtrated through celite and the filtrate immediately combined with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.71 g, 3.45 mmol),1-hydroxybenzotriazole (0.46 g, 3.40 mmol), the product of Preparation1j (1.30 g, 3.44 mmol) and additional tetrahydrofuran (60 mL). Afterstirring overnight at ambient temperature, the mixture was concentratedand the residue slurried in ethyl acetate then filtered. The filtratewas concentrated and the residue purified by flash chromatography(silica gel, chloroform/methanol) which afforded 1.50 g (66%) of thedesired product which was used without further purification.

Example 8

To a solution of the product of Preparation 14 (1.45 g, 2.20 mmol) indichloromethane (30 mL) was added triflouroacetic acid (10 mL). After 2h, the mixture was concentrated and the residue treated with excessaqueous sodium bicarbonate and extracted. The combined organic extractswere concentrated and the resulting residue was purified by flashchromatography (silica gel, chloroform/methanol) to provide 0.68 g ofthe desired product as a yellow solid: MS: (M+H)⁺ 561.3. ¹H NMR wasconsistent with product. Anal. Calcd. for C₃₁H₄₀N₆O₄.0.2 CHCl3: C,64.11; H, 6.93;N, 14.38. Found: C, 64.19; H, 7.19; N, 14.50. Theisomeric mixture (1.72 g) was separated as previously described inExample 7 to provide 0.64 g of isomer 1 (t_(R)=7.50 min) and 0.49 g ofisomer 2 (t_(R)=10.15 min). Isomer 2 (486 mg, 0.87 mmol) was dissolvedin a minimal amount of ehtyl acetate and treated with an excess ofsaturated hydrochloric acid in ethyl acetate. Concentration andsubsequent evaporation from diethyl ether allowed for recovery of 580 mgof an off-white solid: MS: (M+H)⁺ 561.3, 562.4. ¹H NMR was consistentwith product. Anal. Calcd. for C₃₁H₄₀N₆O₄.3.0 HCl: C, 55.57; H, 6.47; N,12.54. Found: C, 56.40; H, 6.43; N, 12.20.

The product of Preparation 13 (0.85 g, 2.57 mmol) was combined with 10%palladium/carbon (0.50 g) and palladium/black (0.15 g) intetrahydrofuran (40 mL) and the mixture shaken under a hydrogenatmosphere (38 mm Hg) in a Parr apparatus. After reduction was complete,the catalyst was removed by filtration through celite and theamine/tetrahydrofuran solution was immediately combined with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(0.53 g, 2.57 mmol),1-hydroxybenzotriazole (0.35 g, 2.57 mmol), the product of Preparation1L (1.00 g, 2.57 mmol) and additional tetrahydrofuran (60 mL). Afterstirring overnight at ambient temperature, the mixture was concentratedand the residue slurried in ethyl acetate and filtered. The filtrate wasconcentrated and the residue purified by flash chromatography(silicagel, chloroform/methanol) which gave 1.62 g of the desired product whichwas used without further purification.

Example 9

The compound of Preparation 15 (1.57 g, 2.34 mmol) was dissolved indichloromethane (25 mL) and triflouroacetic acid (10 mL) added. Theresulting mixture was stirred at ambient temperature for 2.5 h,concentrated, and the residue treated with excess aqueous sodiumbicarbonate. The aqueous mixture was extracted with ethyl acetate andthe combined organic extracts concentrated and dried. The residue waschromatographed over silica gel (chloroform/methanol) to provide 0.71 g(53%) of the desired product: MS: (M+H)⁺ 572.5. ¹H NMR was consistentwith product. Anal. Calcd. for C₃₁H₃₇N₇O₄.0.35 CHCl₃: C, 61.38; H, 6.14;N, 15.98. Found: C, 61.36; H, 6.11; N, 16.08. The isomeric mixture (2.16g) was separated as previously described in Example 7 to provide 1.10 gof isomer 1 (t_(R)=10.34 min) and 0.80 g of isomer 2 (t_(R)=13.70 min).The product derived from isomer 2 (0.80 g, 1.40 mmol) was dissolved in aminimal amount of ethyl acetate and the resulting solution treated withan excess of hydrochloric acid in ethyl acetate. The solution was thenconcentrated to provide 0.88 g (82%) of the desired product as an offwhite solid: MS: (M+H)⁺ 572.3, 573.4. ¹H NMR was consistent withproduct. Anal. Calcd. for C₃₁H₃₇N₇O₄.3.0 HCl: C, 54.67; H, 5.92; N,14.40. Found: C, 54.25; H, 5.89; N, 13.35.

To a solution of the product of Preparation 3 -411159-(5.75 g,18.9 mmol)stirring at room temperature in tetrahydrofuran (10 mL) was added sodiumhydroxide (25 mL of a 5 N aqueous solution) along with water (15 mL) andethanol (10 mL). After hydrolysis was complete, the mixture wasacidified to pH 2.0 with aqueous hydrochloric acid and extracted. Thecombined organic extracts were dried, filtered, and concentrated to givethe desired product in quantitative yield as a tan solid: ¹H NMR (300MHz, DMSO-d₆) δ14.05-13.60 (bs, 1H), 8.34 (s, 1H) 7.90 (s, 1H), 7.45 (d,2H, J=8.67 Hz), 7.00 (d, 2H, J=8.67 Hz), 6.42 (s, 1H), 3.77 (s, 3H).FDMS: 277 (M)⁺ Anal. Calcd. for C₁₂H₁₁N₃O₅.0.67 H₂O: C, 49.82; H,4.30;N, 14.52. Found: C, 50.05; H, 4.01; N, 14.12.

The compound of Preparation 16 (2.50 g,9.0 mmol) was combined withaqueous dimethylamine(40%,1.15 mL,9.0 mmol), 1-hydroxy-benzotriazolehydrate(1.22 g, 9.0 mmol)and 1,3-dicyclohexylcarbodiimide (1.86 g, 9.0mmol) in tetrahydrofuran (60 mL) and the mixture stirred at ambienttemperature. After 18 h, the mixture was concentrated and the residueslurried in ethyl acetate and filtered. The filtrate was concentratedand the resulting residue purified by flash chromatography (silica gel,chloroform/methanol) to afford 1.83 g (67%) of the desired product: ¹HNMR (300 MHz, DMSO-d₆) δ8.14 (s, 1H) 7.76 (s, 1H), 7.42 (d, 2H, J=8.67Hz), 7.00 (d, 2H, J=8.67 Hz), 6.78 (s, 1H), 3.77 (s, 3H), 2.91 (2, 3H),2.85 (s, 3H). ESMS: (M+H)⁺ 305.2.

The compound of Preparation 17 (1.26 g, 4.14 mmol) was combined with 10%palladium/carbon (0.70 g) and palladium/black (0.15 g) intetrahydrofuran(40 mL) and the mixture shaken under a hydrogenatmosphere (38 mm Hg) in a Parr apparatus. After reduction was complete,the catalyst was removed by filtration through celite and the solutionwas immediately combined with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.82 g, mmol),1-hydroxybenzotriazole mono-hydrate (0.54 g, 4.0 mmol), the product ofPreparation 1j, (1.50 g, 397 mmol), and additional tetrahydrofuran (60mL). After stirring overnight at ambient temperature, the mixture wasconcentrated and the resulting residue slurried in ethyl acetate andfiltered. The filtrate was concentrated and the residue purified bysilica gel chromatography (chloroform/methanol) which provided 1.50 g(57%) of the desired product. MS: (M+H)⁺ 635.6. ¹H NMR was consistentwith product. Anal. Calcd. for C₃₄H₄₆N₆O₆: C, 64.33; H, 7.30; N, 13.24.Found: C, 64.09; H, 7.09; N, 13.01.

Example 10

To a solution of the compound of preparation 18 (1.45 g, 2.29 mmol)stirring in dichloromethane (50 mL) at room temperature was addedtriflouroacetic acid (15 mL). After 3 h, the reaction mixture wasconcentrated and the residue treated with excess aqueous sodiumbicarbonate. The mixture was extracted with ethyl acetate and thecombined organic extracts were dried over sodium sulfate andconcentrated. The residue was purified by flash chromatography (silicagel, chloroform/methanol) to give 0.73 g (60%) if the desired product asa yellow solid: (60%. ESMS: (M+H)⁺ 535.4. ¹H NMR was consistent withproduct. Anal. Calcd. for C₂₉H₃₈N₆O₄.0.05 CHCl3: C, 64.54; H, 7.09; N,15.54. Found: C, 64.28; H, 6.70; N, 15.35.

The diastereomeric mixture (2.35 g) was resolved by HPLC (8×15 cmProchrom column packed with Kromosil CHI-DMP chiral phase using aneluent mixture of 3A alcohol and dimethylethylamine in heptane toprovide the individual diastereomers in pure form (isomer 1, t_(R)=7.84min), isomer 2 (1.03 g, t_(R)=10.27 min). To a solution of isomer 2(1.03 g, 1.93 mmol) in ethyl acetate was added a saturated solution ofhydrochloric acid in ethyl acetate. The resulting solution wasconcentrated, treated with diethyl ether and concentrated to provide1.23 g of the desired product as an off white solid: ESMS: (M+H)⁺ 535.3,536.4. ¹H NMR was consistent with product. Anal. Calcd. forC₂₉H₃₈N₆O₄.3.0 HCl: C, 54.08; H, 6.42; N, 13.05. Found: C, 54.12; H,6.38; N, 12.86.

The compound of preparation 17 (0.73 g, 2.38 mmol) was combined with 10%palladium/carbon (0.50 g) and palladium/black (0.10 g) intetradyrofuran(40 mL) and the mixture shaken under hydrogen (38 mm Hg)in a Parr apparatus. After reduction was complete, the catalyst wasremoved by filtration through celite and the resulting solution wasimmediately combined with dicyclohexylcarbodiimide (0.49 g, 2.38 mmol),1-hydroxybenzotriazole mono-hydrate (0.32 g, 2.37 mmol), the product ofPreparation 1L (0.93 g, 2.39 mmol) and additional tetrahydrofuran (60mL). After stirring overnight at ambient temperature, the mixture wasconcentrated and the residue slurried in ethyl acetate and filtered. Thefiltrate was concentrated and the residue purified by silica gelchromatography(chloroform/methanol) to provide 0.76 g (50%) of thedesired product as an off white solid which was used without furtherpurification.

Example 11

To a solution of the compound of preparation 19 (0.74 g, 1.15 mmol)stirring at room temperature in dichloromethane (30 mL) was addedtriflouroacetic acid (10 mL). After 2 h, the mixture was concentratedand the residue treated with excess aqueous sodium bicarbonate. Theresulting mixture was extracted with ethyl acetate and the combinedorganic extracts were concentrated. The residue was purified by flashchromatography (silica gel, chloroform/methanol) to provide 0.23 g (37%)of the desired product: ESMS: (M+H)⁺ 546.6. ¹H NMR was consistent withproduct. Anal. Calcd. for C₂₉H₃₅N₇O₄.0.25 CHCl3: C, 61.05; H, 6.17; N,17.04. Found: C, 61.41; H, 6.32; N, 16.52. The isomeric mixture (2.00 g)was separated as described in Example 10 to provide 0.73 g of isomer 1(t_(R)=9.85 min) and 0.82 g of isomer 2 (t_(R)=12.87 min). To a solutionof isomer 2 (0.82 g, 1.50 mmol) stirring in ethyl acetate and methanolwas added a saturated solution of hydrochloric acid in ethyl acetate.The resulting mixture was concentrated to provide 0.84 g of the desiredproduct: ESMS: (M+H)⁺ 546.2, 547.3. ¹H NMR was consistent with product.Anal. Calcd. for C₂₉H₃₅N₇O₄.3.0 HCl: C, 53.18; H, 5.85; N, 14.97. Found:C, 53.73; H, 6.03; N, 14.04.

Reaction of (3,4-dimethoxyphenyl)acetic acid (30.0 g, 153 mmol) andp-toluenesulfonic acid (6.5 g, 33.8 mmol) in absolute ethanol (200 mL)according to Preparation 1 gave 31.6 g (92%) of the desired product as ayellow oil: ¹H-NMR is consistent with structure; MS (ion spray) 225(M+1); Anal. Calc'd for C₁₂H₁₆O₄: C, 64.27; H, 7.19. Found: C, 64.08; H,7.07.

Reaction of the compound of Preparation 20 (1.5 g, 6.7 mmol),N-bromosuccinimide (1.3 g, 7.4 mmol), 2,2′-azobis(2-methylpropionitrile)(0.2 g) in carbon tetrachloride (30 mL) as decribed in Preparation 2provided 2.03 g (100%) of the desired product as a clear oil: ¹H-NMR isconsistent with structure; Anal. Calc'd for C₁₂H₁₅BrO₄: C, 47.54; H,4.99. Found: C, 47.64; H, 5.17.

Reaction of the product of Preparation 21 (13.3 g, 44 mmol),4-nitroimidazole (5.0 g, 44 mmol) and sodium hydride (2.1 g, 53 mmol) intetrahydrofuran (400 mL) as desribed in Preparation 3 provided 22.6 g(85%) of the desired product as a tan oil. ¹H-NMR is consistent withstructure; MS (ion spray) 334.1 (M−1); Anal. Calc'd forC₁₅H₁₇N₃O₆.0.1CHCl3: C, 52.23; H, 4.96; N, 12.10. Found: C, 52.55; H,4.81; N, 11.85.

Hydrogenation of the compound of Preparation 22 (2.1 g, 6.3 mmol) with10% palladium on carbon (1.5 g) in tetrahydrofuran (100 mL) followed byreaction with the product of Preparation 1d (2.4 g, 6.3 mmol),1-hydroxybenzotriazole (0.97 g, 6.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.43 g, 6.9 mmol) asdescribed in Preparation 4 gave 2.08 g (49%) of the desired product as ared foam: ¹H-NMR is consistent with structure; MS (ion spray) 668.4(M+1).

Reaction of the product of Preparation 23 (426814) (1.93 g, 2.9 mmol)and lithium hydroxide (0.08 g, 3.5 mmol) in dioxane (50 mL)and water (25mL) as described in Preparation 5 provided 1.68 g (91%) of the desiredproduct as a tan foam: ¹H-NMR is consistent with structure; MS (ionspray) 640.3 (M+1); Anal. Calc'd for C₃₂H₄₁N₅O₉: C, 60.08; H, 6.46; N,10.95. Found: C, 60.31; H, 6.75; N, 10.65.

Reaction of the product of Preparation 25 (426815) (0.8 g, 1.3 mmol),4-methylpiperidine (0.16 mL, 1.3 mmol), 1-hydroxybenzotriazole (0.2 g,1.43 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.3 g,1.43 mmol) in dimethylformamide (20 mL) as desribed in Preparation 6provided 0.56 g (60%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (ion spray) 721.5 (M+1); Anal. Calc'd forC₃₈H₅₂N₆O₈: C, 63.31; H, 7.27; N, 11.66. Found: C, 63.18; H, 7.30; N,11.60.

Example 12

Reaction of the compound of Preparation 25 (0.5 g, 0.7 mmol andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.4 g (83%) of the desired mixture of isomers as a whitesolid: ¹H-NMR is consistent with structure; MS (ion spray) 621.6 (M+1);Anal. Calc'd for C₃₃H₄₄N₆O₆.2.3hydrochloric acid: C, 56.25; H, 6.62; N,11.93. Found: C, 56.39; H, 6.33; N, 11.83.

Reaction of the the product of Preparation 24 (0.8 g, 1.3 mmol),dimethylamine hydrochloride (0.11 g, 1.3 mmol), triethylamine (0.2 mL,1.43 mmol), 1-hydroxybenzotriazole (0.2 g, 1.43 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.3 g, 1.43 mmol) indimethylformamide (20 mL) as described in Preparation 6 gave 0.3 g (35%)of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (ion spray) 667.4 (M+1); Anal. Calc'd for C₃₄H₄₆N₆O₈: C,61.25; H, 6.95; N, 12.60. Found: C, 60.83; H, 6.48; N, 12.45.

Example 13

Reaction of the product of Preparation 26 (0.28 g, 0.42 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.21 g (78%) of the desired mixture of isomers as a whitesolid: ¹H-NMR is consistent with structure; MS (high res) calc'd forC₂₉H₃₉N₆O₆: 567.2931. Found: 567.2938. Anal. Calc'd forC₂₉H₃₈N₆O₆.2hydrochloric acid: C, 54.46; H, 6.30; N, 13.14. Found: C,54.67; H, 6.08; N, 13.00.

Reaction of 4-trifluoromethylphenyl acetic acid (15.0 g, 73.4 mmol) andp-toluenesulfonic acid (2.8 g, 14.7 mmol) in absolute ethanol (100 mL)as described in Preparation 1 gave 16.3 g (95%) of the desired productas colorless oil: ¹H-NMR (d, DMSO) 1.18 (t, J=7.0 Hz, 3H), 3.80 (s, 2H),4.10 (q, J=7.0 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.69 (d, J=7.9 Hz, 2H);MS (FD) 232 (M+); Anal. Calc'd for C₁₁H₁₁F₃O₂: C, 56.90; H, 4.77. Found:C, 56.81; H, 4.85.

Reaction of the product of Preparation of 27 (15.8 g, 68.0 mmol),N-bromosuccinimide (12.5 g, 70 mmol) and 48% HBr (3 drops) in carbontetrachloride (80 mL) as described in Preparation 2 gave 19.8 g (94%) ofthe desired product as a colorless oil: ¹H-NMR (d, DMSO) 1.19 (t, J=7.2Hz, 3H), 4.15-4.25 (m, 2H), 6.07 (s, 1H), 7.78 (s, 4H); MS (FD) 309, 311(M+); Anal. Calc'd for C₁₁H₁₀BrF₃O₂: C, 42.47; H, 3.24. Found: C, 42.38;H, 3.13.

Reaction of the product of Preparation 28 (51.8 g, 167 mmol),4-nitroimidazole (18.8 g, 167 mmol), and potassium carbonate (51 g, 368mmol) in N,N-dimethylformamide (600 mL) as described Preparation 3 gave21.7 g (38%) of the desired product as a viscous orange oil: ¹H-NMR (d,DMSO) 1.19 (t, J=7.2 Hz, 3H), 4.26 (q, J=7.2 Hz, 2H), 6.80 (s, 1H), 7.76(d, J=8.3 Hz, 2H), 7.83 (d, J=8.3 Hz, 2H), 8.01 (s, 1H), 8.51 (s, 1H);MS (ion spray) 344 (M+1); Anal. Calc'd for C₁₄H₁₂F₃N₃O₄: C, 48.99; H,3.52; N, 12.24. Found: C, 49.03; H, 3.74; N, 11.96.

Hydrogenation of the product of Preparation 29 (8.5 g, 24.8 mmol) with10% palladium on carbon (6.0 g) in tetrahydrofuran (70 mL) followed bycoupling with the product of Preparation 1d (9.5 g, 24.8 mmol),1-hydroxybenzotriazole (3.7 g, 27.3 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.6 g, 27.3 mmol)asdescribed in Preparation 4 gave 12.8 g (77%) of the desired product as atan foam: ¹H-NMR (d, DMSO) 1.17 (t, J=7.2 Hz, 3H), 1.25-1.35 (m, 15H),3.60 (m, 1H), 3.70 (m, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.44 (d, J=2.6 Hz,2H), 4.60 (m, 1H), 6.63 (s, 1H), 7.23-7.30 (m, 7H), 7.45 (m, 1H),7.58-7.65 (m, 3H), 7.81 (d, J=8.3 Hz, 2H), 10.25 (br s, 1H); MS (ionspray) 676.5 (M+1); Anal. Calc'd for C₃₃H₄₀F₃N₅O₇: C, 58.66; H, 5.97; N,10.36. Found: C, 58.58; H, 6.17; N, 10.27.

Reaction of the product of Preparation 30 (12.3 g, 18.2 mmol) andlithium hydroxide (0.52 g, 21.8 mmol) in dioxane (100 mL) and water (75mL) as described in Preparation 5 gave 11.8 g (100%) of the desiredproduct as tan foam: ¹H-NMR (d, DMSO) 1.20-1.35 (m, 15 H), 3.60 (m, 1H),3.65 (m, 1H), 4.45 (d, J=2.6 Hz, 2H), 4.60 (m, 1H), 6.46 (s, 1H), 7.15(m, 1H), 7.20-7.35 (m, 6H), 7.42 (m, 1H), 7.57-7.65 (m, 3H), 7.79 (d,J=8.3 Hz, 2H), 10.25 (br s, 1H); MS (ion spray) 648.9 (M+1); Anal.Calc'd for C₃₁H₃₆F₃N₅O₇: C, 57.41; H, 5.60; N, 10.81. Found: C, 57.31;H, 5.59; N, 10.53.

Reaction of the product of Preparation 31 (8.0 g, 12.3 mmol),4-methylpiperidine (1.5 mL, 12.3 mmol), 1-hydroxybenzotriazole (1.83 g,13.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.8 g,13.5 mmol) in N,N-dimethylformamide (150 mL) as described in Preparation6 gave 7.33 g (81%) of the desired product as a tan foam: ¹H-NMR (d,DMSO) 0.78 (d, J=6.0 Hz, 1.5H), 0.84 (d, J=6.0 Hz, 1.5H), 0.95 (m, 1H),1.25-1.35 (m, 16H), 1.50-1.70 (m, 4H), 2.65 (m, 1H), 3.60 (m, 1H), 3.67(m, 1H), 3.80 (m, 1H), 4.35-4.50 (m, 3H), 4.60 (m, 1H), 6.88 (d, J=9.8Hz, 1H), 7.20-7.30 (m, 7H), 7.45 (m, 1H), 7.48-7.55 (m, 2H), 7.60 (m,1H), 7.75-7.85 (m, 2H), 10.25 (br s, 1H); MS (ion spray) 729 (M+1);Anal. Calc'd for C₃₇H₄₇F₃N₆O₆: C, 60.98; H, 6.50; N, 11.53. Found: C,61.24; H, 6.44; N, 11.77.

Example 14 and 15

Reaction of the product of Preparation 32 (7.0 g, 10.0 mmol) andtrifluoroacetic acid (10 mL) in dichloromethane (25 mL) as described inExample 1 gave 5.62 g (93%) of the desired product (3.0 g) as a tan foamwhich was purified by HPLC (8×15 cm Prochrom column packed with KromosilCHI-DMP chiral phase with an eluent mixture of 3A alcohol anddimethylethylamine in heptane) to give 1.5 g (45%) of isomer 1 and 1.1 g(30%) of isomer 2.

Example 14 (isomer 1): ¹H-NMR (d, DMSO) 0.25 (m, 1H), 0.76 (d, J=6.4 Hz,1.5H), 0.86 (d, J=6.4 Hz, 1.5H), 1.00 (m, 1H), 1.45-1.70 (m, 8H),2.65-2.75 (m, 2H), 3.15 (m, 1H), 3.65-3.80 (m, 3H), 4.40 (m, 1H), 4.51(s, 2H), 4.75 (m, 2H), 7.10 (d, J=12.8 Hz, 1H), 7.20-7.40 (m, 6H), 7.58(d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.80-7.90 (m, 2H), 8.10 (brs, 1H), 8.20-8.35 (m, 3H), 8.55 (d, J=7.5 Hz, 1H), 10.95 (br s, 1H);t_(R)=8.23 min; MS (ion spray) 629.3 (M+1); Anal. Calc.d forC₃₂H₃₉F₃N₆O₄.2HCl: C, 54.78; H, 5.89; N, 11.98. Found: C, 54.85; H,5.71; N, 11.70.

Example 15 (isomer 2): ¹H-NMR (d, DMSO) 0.25 (m, 1H), 0.76 (d, J=6.4 Hz,1.5H), 0.86 (d, J=6.4 Hz, 1.5H), 1.00 (m, 1H), 1.45-1.70 (m, 8H),2.65-2.75 (m, 2H), 3.15 (m, 1H), 3.65-3.80 (m, 3H), 4.40 (m, 1H), 4.51(s, 2H), 4.75 (m, 2H), 7.10 (d, J=12.8 Hz, 1H), 7.20-7.40 (m, 6H), 7.58(d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.80-7.90 (m, 2H), 8.10 (brs, 1H), 8.20-8.35 (m, 3H), 8.55 (d, J=7.5 Hz, 1H), 10.95 (br s, 1H);t_(R)=10.77 min; MS (ion spray) 629.3 (M+1); Anal. Calc.d forC₃₂H₃₉F₃N₆O₄.2.2HCl: C, 54.22;H, 5.86; N, 11.85. Found: C, 54.15; H,5.84; N, 11.64.

Reaction of the product of Preparation 31 (0.6 g, 0.93 mmol),4-(4-fluorobenzoyl)piperidine hydrochloride (0.23 g, 0.93 mmol),triethylamine (0.15 mL, 10.2 mmol), 1-hydroxybenzotriazole (0.14 g, 1.02mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.21 g, 1.02mmol) in dimethylformamide (30 mL) as described in Preparation 6provided in 0.35 g (45%) of the desired product as a yellow foam: ¹H-NMR(d, DMSO) 1.25-1.35 (m, 15H), 1.40-1.50 (m, 2H), 1.75 (m, 1H), 1.85 (m,1H), 2.85-3.00 (m, 2H), 3.55-3.75 (m, 3H), 3.90 (m, 1H), 4.40-4.50 (m,3H), 4.60 (m, 1H), 6.90 (m, 1H), 7.25-7.40 (m, 12H), 7.50-7.60 (m, 3H),8.03-8.10 (m, 2H), 10.20 (br s, 1H); MS (ion spray) 837.4 (M+1); Anal.Calc'd for C₄₃H₄₈F₄N₆O₇: C, 61.71; H, 5.78; N, 10.04. Found: C, 61.53;H, 5.98; N, 9.95.

Example 16

Reaction of the product of Preparation 33 (0.34 g, 0.4 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.2 g (63%) of the desired product as a yellow solid:¹H-NMR (d, DMSO) 1.45-1.65 (m, 6H), 1.75 (m, 1H), 1.85 (m, 1H),2.85-3.05 (m, 2H), 3.25 (m, 1H), 3.60-4.00 (m, 7H), 4.40-4.55 (m, 3H),4.75 (m, 1H), 7.05 (d, J=10.6 Hz, 1H), 7.25-7.40 (m, 8H), 7.55-7.70 (m,2H), 7.75-7.85 (m, 2H), 8.00-8.10 (m, 2H), 8.15-8.25 (m, 3H), 8.50 (d,J=7.2 Hz, 1H), 10.75 (br s, 1H); MS (ion spray) 737.0 (M+1); Anal.Calc'd for C₃₈H₄₀F₄N₆O₅.2.4HCl: C, 55.37; H, 5.18; N, 10.20. Found: C,55.39; H, 5.45; N, 10.07.

Hydrogenation of the product of Preparation 29 (1.75 g, 5.1 mmol) with10% palladium on carbon (1.4 g) in tetrahydrofuran (60 mL) followed byreaction with the product of Preparation 1L (2.0 g, 5.1 mmol),1-hydroxybenzotriazole (0.76 g, 5.6 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.16 g, 5.6 mmol) asdescribed in Preparation 4 gave 2.51 g (72%) of the desired product as atan foam: ¹H-NMR (d, DMSO) 1.15-1.35 (m, 18H), 3.05-3.15 (m, 2H), 4.25(m, 2H), 4.65 (br s, 1H), 6.62 (s, 1H), 6.85 (m, 1H), 6.95-7.08 (m, 2H),7.20-7.30 (m, 2H), 7.40-7.55 (m, 2H), 7.55-7.65 (m, 3H), 7.82 (d, J=8.3Hz, 2H), 10.20 (br s, 1H), 10.75 (br s, 1H); MS (ion spray) 685 (M+1);Anal. Calc'd for C₃₄H₃₉F₃N₆O₆.1H₂O: C, 58.11; H, 5.88; N, 11.96. Found:C, 58.15; H, 5.59; N, 11.92.

Reaction of the product of Preparation 34 (2.2 g, 3.2 mmol) and lithiumhydroxide (0.1 g, 3.9 mmol) in dioxane (50 mL) and water (25 mL) asdescribed in Preparation 5 gave 2.1 g (100%) of the desired product as atan foam: ¹H-NMR (d, DMSO), 1.15-1.35 (m, 15H), 3.05-3.15 (m, 2H), 4.65(br s, 1H), 6.97 (s, 1H), 6.90 (m, 1H), 6.98-7.10 (m, 2H), 7.20-7.30 (m,2H), 7.40-7.55 (m, 2H), 7.57-7.64 (m, 3H), 7.80 (d, J=8.3 Hz, 2H), 10.20(br s, 1H), 10.75 (br s, 1H), 13.80 (br s, 1H); MS (ion spray) 657.4(M+1); Anal. Calc'd for C₃₂H₃₅F₃N₆O₆: C, 58.53; H, 5.37; N, 12.80.Found: C, 59.28; H, 5.17; N, 12.65.

Reaction of the product of Preparation 35 (0.7 g, 1.1 mmol),4-methylpiperidine (0.13 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.17 g,1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.26 g, 1.2mmol) in N,N-dimethylformamide (30 mL) as described in Preparation 6provided 0.47 g (58%) of the desired product as a tan foam: ¹H-NMR (d,DMSO) 0.78 (d, J=6.4 Hz, 1.5H), 0.86 (d, J=6.3 Hz, 1.5H), 1.15-1.35 (m,18H), 1.50-1.70 (m, 3H), 2.60-2.70 (m, 2H), 3.00-3.15 (m, 2H), 3.30 (m,1H), 4.40 (m, 1H), 4.65 (m, 1H), 6.85-6.95 (m, 2H), 7.00-7.10 (m, 2H),7.17-7.30 (m, 2H), 7.40-7.60 (m, 4H), 7.75-7.85 (m, 2H), 10.20 (br s,1H), 10.75 (br s, 1H); MS (ion spray) 738.5 (M+1); Anal. Calc'd forC₃₈H₄₆F₃N₇O₅.1H₂O: C, 60.39; H, 6.40; N, 12.97. Found: C, 60.18; H,6.21; N, 12.99.

Examples 17 and 18

Reaction of the product of Preparation 36 (4.8 g, 6.5 mmol) andtrifluoroacetic acid (16 mL) in dichloromethane (40 mL) as described inExample 1 gave 2.0 g (44%) of the desired mixture as a tan foam.Purification by HPLC (8×15 cm Prochrom column packed with KromosilCHI-DMP chiral phase with an eluent mixture of 3A alcohol (13% by v),dimethylethylamine (0.2% by v) in heptane at a flow rate of 250 mL/min)gave 0.5 g (12%) of isomer 1 and 0.4 g (9%) of isomer 2.

Example 17. (isomer 1) ¹H-NMR (d, DMSO) 0.77 (d, J=6.5 Hz, 1.5H), 0.87(d, J=6.0 Hz, 1.5H), 1.00 (m, 1H), 1.32 (s, 3H), 1.50 (s, 3H), 1.50-1.70(m, 2H), 2.72 (m, 1H), 3.00-3.30 (m, 4H), 3.75 (m, 1H), 4.05-4.33 (m,3H), 4.20 (m, 1H), 4.78 (m, 1H), 6.94 (m, 3H), 7.20 (s, 1H), 7.30-7.40(m, 2H), 7.55-7.70 (m, 2H), 7.75-8.00 (m, 4H), 8.05-8.15 (m, 2H), 8.50(m, 1H), 10.86 (s, 1H), 11.05 (s, 1H); t_(R)=6.01 min; MS (ion spray)638.2 (M+1).

Example 18. (isomer 2) ¹H-NMR (d, DMSO) 0.77 (d, J=6.5 Hz, 1.5H), 0.87(d, J=6.0 Hz, 1.5H), 1.00 (m, 1H), 1.32 (s, 3H), 1.50 (s, 3H), 1.50-1.70(m, 2H), 2.72 (m, 1H), 3.00-3.30 (m, 4H), 3.75 (m, 1H), 4.05-4.33 (m,3H), 4.20 (m, 1H), 4.78 (m, 1H), 6.94 (m, 3H), 7.20 (s, 1H), 7.30-7.40(m, 2H), 7.55-7.70 (m, 2H), 7.75-8.00 (m, 4H), 8.05-8.15 (m, 2H), 8.50(m, 1H), 10.86 (s, 1H), 11.05 (s, 1H); t_(R)=7.5 min; MS (ion spray)638.2 (M+1).

A mixture of the product of Preparation of 29 (11.1 g, 32.3 mmol) and 5%palladium on carbon (1.7 g) in tetrahydrofuran (100 mL) was hydrogenatedat 60 psi at room temperature using a Parr apparatus. After 1.5 h, theresulting brown solution was filtered through celite and concentrated togive 8.8 g (87%) crude oil which was used without purification. To amixture of the amine stirring at 0° C. in tetrahydrofuran (20 mL) wasadded the product of Preparation 1j (10.6 g, 28.1 mmol) intetrahydrofuran (30 mL). To this mixture was added1-hydroxy-7-azobenzotriazole (4.0 g, 29.5 mmol) and1,3-dicyclohexylcarbodiimide (6.1 g, 29.5 mmol). The solution wasallowed to warm to room temperature and the resulting mixture filteredafter 3 days. The filtrate was concentrated and subsequently purified byflash chromatography (silica gel, 3.5% methanol/dichloromethane) toprovide 12.1 g (64%) of the desired product as an orange solid: ¹H-NMR(d, DMSO) 1.15 (t, J=7 Hz, 3H), 1.18-1.32 (m, 15H), 1.35-1.70 (m, 4H),3.23 (m, 2H), 4.19 (q, J=7 Hz, 2H), 4.31 (m, 1H), 6.58 (s, 1H), 7.00 (brs, 1H), 7.05-7.22 (m, 6H), 7.41 (m, 1H), 7.52-7.58 (m, 3H), 7.75 (d, J=8Hz, 2H), 10.19 (br s, 1H); MS (ion spray) 674.7 (M+1); Anal. Calc'd forC₃₄H₄₂F₃N₅O₆: C, 60.61; H, 6.28; N, 10.39. Found: C, 60.44; H, 6.48; N,10.36.

To a solution of the product of Preparation 37 (12.0 g, 17.8 mmol)stirring in dioxane (20 ml) and water (20 ml) at room temperature wasadded lithium hydroxide (0.84 g, 35.6 mmol). After 90 min withintermittent sonication, the reaction was poured into a solution ofsodium bisulfate (12 g/50 mL H₂O) and brine (20 mL) then extracted withethyl acetate. The combined organic extracts were dried over sodiumsulfate, filtered, and concentrated to provide 11.5 g (100%) of thedesired product as a tan solid: ¹H-NMR (d, DMSO) 1.17-1.31 (m, 15 H),1.40-1.70 (m, 4H), 2.45 (m, 2H), 4.33 (m, 1H), 6.40 (s, 1H), 7.00 (m,1H), 7.05-7.23 (m, 6H), 7.40 (m, 1H), 7.55-7.71 (m, 3H), 7.76 (d, J=8Hz, 2H), 10.25 (br s, 1H); MS (ion spray) 646.6 (M+1); Anal. Calc'd forC₃₂H₃₈F₃N₅O₆.0.7 H₂O: C, 58.39; H, 6.03; N, 10.64. Found: C, 58.52; H,6.01; N, 9.87*.

To a solution of the product of Preparation 38 (6.0 g, 9.3 mmol)stirring at 0° C. in dimethylformamide was added dimethylaminehydrochloride (0.76 g, 9.3 mmol), diethylcyanophosphonate (1.41 mL, 9.3mmol), and triethylamine (1.29 mL, 9.3 mmol). After 30 min, a secondequivalent of dimethylamine hydrochloride, DECP and triethylamine wereadded. After 30 min, the reaction mixture was diluted with ethyl acetate(300 mL) and washed with aqueous sodium bisulfate and brine. The organicextract was dried over sodium sulfate, filtered, and concentrated. Theresulting crude material was purified by radial chromatography (silicagel, 4% methanol in dichloromethane) to give 4.7 g (75%) of the desiredproduct as a tan foam: ¹H-NMR (d, CDCl₃) 1.25(s, 9H), 1.42 (s, 6H),1.60-1.80 (m, 4H), 1.90 (br s, 1H), 2.57 (m, 2H), 2.98 (s, 6H), 4.48 (m,1H), 7.05-7.21 (m, 6H), 7.50(m, 1H), 7.62-7.76 (m, 5H),8.93 (br s, 1H),10.93 (br s, 1H); MS (ion spray) 673.7 (M+1).

Examples 19 and 20

To the product of Preparation 39 (4.7 g, 7.0 nmol) was stirred at roomtemperature in a saturated solution of hydrochloric acid in glacialacetic acid (30 mL). After 90 min, the mixture was concentrated. Theresulting material diluted with ethyl acetate and extracted with aqueoussodium bicarbonate. The organic extract was dried over sodium sulfate,filtered, and concentrated to give 3.7 g (93%) of an orange solid. MS(ion spray) 573.4 (M+1). The diastereomers (3.4 g) were separated bychiral chromatography using a Kromasil-CHI normal phase column toprovide 1.40 g (41%) of isomer 1 and 1.26 g (37%) of isomer 2. Theindividual isomers were dissolved in a saturated solution ofhydrochloric acid in glacial acetic acid (4 mL) and subsequentlyconcentrated to provide the desired products as tan solids:

Example 19 (isomer 1) ¹H-NMR (d, DMSO) 1.41 (s, 3H), 1.42 (s, 3H),1.51-1.73 (m, 4H), 2.53 (m, 2H), 2.82 (s, 3H), 2.84 (s, 3H), 4.39 (m,1H), 6.91 (s, 1H), 7.10 (m, 3H), 7.18-7.29 (m, 3H), 7.55 (d, J=8 Hz,2H), 7.78 (d, J=8 Hz, 2H), 7.91 (br s, 1H), 8.15 (br s, 3H), 8.38 (d,J=7.5 Hz, 1H), 10.78 (br s, 1H); MS (ion spray) 573.4 (M+1); Anal.Calc.d for C₂₉H₃₅F₃N₆O₃.2.3HCl: C, 53.06; H, 5.73; N, 12.80. Found: C,52.90; H, 5.66; N, 12.70.

Example 20. (isomer 2) ¹H-NMR (d, DMSO) 1.42 (s, 6H), 1.51-1.73 (m, 4H),2.53 (m, 2H), 2.82 (s, 3H), 2.84 (s, 3H), 4.39 (m, 1H), 6.91 (s, 1H),7.10 (m, 3H), 7.18-7.29 (m, 3H), 7.55 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz,2H), 7.91 (br s, 1H), 8.15 (br s, 3H), 8.38 (d, J=7.5 Hz, 1H), 10.78 (brs, 1H); MS (ion spray) 573.4 (M+1); Anal. Calc.d for C₂₉H₃₅F₃N₆O₃.2HCl:C, 53.96;H, 5.78; N, 13.02. Found: C, 53.84; H, 5.71; N, 12.93.

Reaction of (2-fluoro-4-trifluoromethyl)phenylacetic acid (20.0 g, 90mmol) and p-toluenesulfonic acid (5.0, 26 mmol) in absolute ethanol (200mL) as described in Preparation 1 provided 22.5 g (100%) of the desiredproduct as a colorless oil: ¹H-NMR is consistent with structure; MS (FD)250 (M+); Anal. Calc'd for C₁₁H₁₀F₄O₂: C, 52.81; H, 4.03. Found: C,52.94; H, 3.94.

Reaction of the product of Preparation 40 (16.8 g, 67 mmol),N-bromosuccinimide (12.3 g, 69 mmol) and 48% HBr (3 drops) in carbontetrachloride (170 mL) as described in Preparation 2 gave 22.05 g (100%)of the desired product as a colorless oil: ¹H-NMR is consistent withstructure; MS (FD) 328, 330 (M+); Anal. Calc'd for C₁₁H₉BrF₄O₂: C,40.15; H, 2.76. Found: C, 40.00; H, 2.77.

Reaction of the product of Preparation 41 (21.4 g, 65 mmol),4-nitroimidazole (8.8 g, 78 mmol) and potassium carbonate (26.8 g, 195mmol) in dimethylformamide (300 mL) as described in Preparation 3 gave3.75 g (16%) of the desired product as a tan oil: ¹H-NMR is consistentwith structure; MS (ion spray) 362.2 (M+1); Anal. Calc'd forC₁₄H₁₁F₄N₃O₄: C, 46.55; H, 3.07; N, 11.63. Found: C, 47.13; H, 3.49; N,11.37.

Reduction of the product of Preparation 42 (2.88 g, 8.0 mmol) with 10%palladium on carbon (1.45 g) in tetrahydrofuran (60 mL) followed bycoupling with the product of Preparation 1d gave (3.0 g, 8.0 mmol),1-hydroxybenzotriazole (1.2 g, 8.8 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (8.8 mmol) as described inPreparation 4 gave 2.85 g (51%) of the desired product as a tan foam:¹H-NMR is consistent with structure; MS (ion spray) 694.4 (M+1); Anal.Calc'd for C₃₃H₃₉F₄N₅O₇: C, 57.14; H, 5.67; N, 10.10. Found: C, 57.28;H, 5.59; N, 10.09.

Reaction of the product of Preparation 43 (2.64 g, 3.8 mmol) and lithiumhydroxide (0.11 g, 4.6 mmol) in dioxane (50 mL) and water (25 mL) asdescribed in Preparation 5 gave 2.53 g (100%) of the desired product asa tan foam. ¹H-NMR is consistent with structure; MS (ion spray) 664.4(M+1)

Reaction of the product of Preparation 44 (0.8 g, 1.2 mmol),4-methylpiperidine (0.14 mL, 1.2 mmol), 1-hydroxybenzotriazole (0.18 g,1.32 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g,1.32 mmol) in dimethylformamide (40 mL) as described in Preparation 6gave 0.63 g (70%) of the desired product as a yellow foam: ¹H-NMR isconsistent with structure; MS (ion spray) 747.4 (M+1).

Example 21

Reaction of the product of Preparation 46 (0.54 g, 0.72 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.4 g (77%) of the desired mixture of isomers as a whitesolid. ¹H-NMR is consistent with structure; MS (ion spray) 647.6 (M+1);Anal. Calc'd for C₃₂H₃₈F₄N₆O₄.2HCl: C, 53.41; H, 5.60; N, 11.68. Found:C, 53.34; H, 5.84; N, 11.65.

Reaction of the product of Preparation 44 (0.8 g, 1.2 mmol),dimethylamine hydrochloride (0.1 g, 1.2 mmol), triethylamine (0.19 mL,1.3 mmol), 1-hydroxybenzotriazole (0.18 g, 1.3 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.3 mmol) indimethylformamide (40 mL) as described in Preparation 6 gave 0.48 g(58%) of the desired product: ¹H-NMR is consistent with structure; MS(ion spray) 693.4 (M+1); Anal. Calc'd for C₃₃H₄₀F₄N₆O₆: C, 57.22; H,5.82; N, 12.13. Found: C, 57.48; H, 5.74; N, 12.02.

Example 22

Reaction of the product of Preparation 46 (0.43 g, 0.62 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.25 g (60%) of the desired product as a mixture ofdiastereoisomers. ¹H-NMR is consistent with structure; MS (ion spray)593.9 (M+1); Anal. Calc'd for C₂₈H₃₂F₄N₆O₄.2hydrochloric acid: C, 50.53;H, 5.15; N, 12.62. Found: C, 50.25; H, 5.20; N, 12.35.

Reaction of 4-fluorophenylacetic acid (15.0 g, 97.0 mmol),p-toluenesulfonic acid (2.0 g, 10.5 mmol) and absolute ethanol (100 mL)as described in Preparation 1 gave 15.4 g (87%) of the desired productas a colorless oil: ¹H-NMR (d, DMSO) 1.17 (t, J=7.2 Hz, 3H), 3.66 (s,2H), 4.06 (q, J=7.2 Hz, 2H), 7.10-7.20 (m, 2H), 7.25-7.35 (m, 2H); MS(FD) 182 (M+); Anal. Calc'd for C₁₀H₁₁FO₂: C, 65.92; H, 6.09. Found: C,65.67; H, 5.96.

Reaction of the product of Preparation 47 (14.9 g, 82 mmol),N-bromosuccinimide (14.9 g, 84.5 mmol) and 48% HBr (4 drops) in carbontetrachloride (80 mL) as described in Preparation 2 gave 18.3 g (85%) ofthe desired product as a colorless oil: ¹H-NMR (d, DMSO) 1.19 (t, J=7.2Hz, 3H), 4.15-4.25 (m, 2H), 5.95 (s, 1H), 7.15-7.30 (m, 2H), 7.56-7.70(m, 2H); MS (FD) 260, 262 (M+); Anal. Calc'd for C₁₀H₁₀BrFO₂: C, 46.00;H, 3.96. Found: C, 46.10; H, 3.95.

Reaction of the product of Preparation 48 (68 g, 260 mmol),4-nitroimidazole (35.0 g, 312 mmol) and potassium carbonate (108 g, 780mmol) in dimethylformamide (300 mL) as described in Preparation 3 gave39.8 g (52%) of the desired product as an orange oil: ¹H-NMR (d, DMSO)1.83 (t, J=7.2 Hz, 3H), 4.25 (q, J=7.2 Hz, 2H), 6.66 (s, 1H), 7.25-7.35(m, 2H), 7.55-7.65 (m, 2H), 7.95 (d, 1.13 Hz, 1H), 8.44 (d, J=1.5 Hz,1H); MS (ion spray) 294.2 (M+1); Anal. Calc'd for C₁₃H₁₂FN₃O₄: C, 53.24;H, 4.12; N, 14.33. Found: C, 53.51; H, 4.07; N, 14.42.

Reduction of the product of Preparation 49 (8.9 g, 30.3 mmol) with 10%palladium on carbon (6.0 g) in tetrahydrofuran (120 mL) followed bycoupling with the product of Preparation 1d (11.4 g, 30 mmol),1-hydroxybenzotriazole (4.5 g, 33 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (6.8 g, 33 mmol) asdescribed in Preparation 4 gave 10.8 g (58%) of the desired product as atan foam: ¹H-NMR (d, DMSO) 1.18 (t, J=7.2 Hz, 3H), 1.25-1.35 (m, 15H),3.60 (m, 1H), 3.70 (m, 1H), 4.25 (q, J=7.2 Hz, 2H), 4.44 (d, J=2.6 Hz,2H), 4.60 (m, 1H), 6.47 (s, 1H), 7.20-7.40 (m, 9H), 7.40-7.50 (m, 3H),7.56 (s, 1H), 10.25 (br s, 1H); MS (ion spray) 626.1 (M+1); Anal. Calc'dfor C₃₂H₄₀FN₅O₇: C, 61.43; H, 6.44; N, 11.19. Found: C, 61.63; H, 6.42;N, 11.26.

Reaction of the product of Preparation 50 (10.5 g, 17.0 mmol) andlithium hydroxide (0.48 g, 20.4 mmol) in dioxane (200 mL) and water (100mL) as described in Preparation 5 gave 10.1 g (100%) of the desiredproduct as a tan foam: ¹H-NMR (d, DMSO) 1.25-1.40 (m, 15H), 3.35 (br s,1H), 3.60 (m, 1H), 3.70 (m, 1H), 4.44 (d, J=2.6 Hz, 2H), 4.60 (m, 1H),6.33 (s, 1H), 7.20-7.35 (m, 9H), 7.40-7.50 (m, 3H), 7.56 (s, 1H), 10.20(br s, 1H); MS (ion spray) 598.5 (M+1); Anal. Calc'd for C₃₀H₃₆FN₅O₇: C,60.29; H, 6.07; N, 11.72. Found: C, 60.38; H, 6.29; N, 11.49.

Reaction of product of Preparation 51 (9.2 g, 15.4 mmol),4-methylpiperidine (1.83 mL, 15.4 mmol), 1-hydroxybenzotriazole (2.3 g,17 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.5 g, 17mmol) in dimethylformamide (100 mL) as described in Preparation 6 gave9.7 g (93%) of the desired product as a tan foam: ¹H-NMR (d, DMSO) 0.76(d, J=6.1 Hz, 1.5H), 0.86 (d, J=6.1 Hz, 1.5H), 1.00 (m, 1H), 1.20-1.40(m, 1SH), 1.45-1.70 (m, 3H), 2.55-2.70 (m, 2H), 3.05 (m, 1H), 3.60 (m,1H), 3.65-3.75 (m, 2H), 4.40 (m, 1H), 4.44 (d, J=2.6 Hz, 2H), 4.60 (m,1H), 6.73 (d, J=11.3 Hz, 1H), 7.15-7.35 (m, 9H), 7.35-7.50 (m, 4H),10.20 (br s, 1H). MS (ion spray) 679.6 (M+1); Anal. Calc'd forC₃₆H₄₇FN₆O₆: C, 63.70; H, 6.98; N, 12.38. Found: C, 63.44; H, 6.86; N,12.22.

Example 23 and 24

Reaction of the product of Preparation 52 (9.7 g, 14.3 mmol) withtrifluoroacetic acid (16 mL) in dichloromethane (40 mL) as described inExample 1 gave 6.8 g (73%) of the desired product as a mixture ofdiastereoisomers. The mixture (3.2 g) was purified by HPLC (8×15 cmProchrom column packed with Kromosil CHI-DMP chiral phase with an eluentmixture of 3A alcohol and dimethylethylamine in heptane) to give 0.8 g(24%) of isomer 1 and 0.9 g (26%) of isomer 2 as white solids:

Example 23 (Isomer 1). ¹H-NMR (d, DMSO) 0.75 (d, J=6.4 Hz, 1.5H), 0.88(d, J=6.4 Hz, 1.5H), 1.10 (m, 1H), 1.35 (m, 1H), 1.45-1.70 (m, 8H),2.60-2.75 (m, 2H), 3.15 (m, 1H), 3.65-3.85 (m, 3H), 4.35 (m, 1H), 4.52(s, 2H), 4.75 (m, 1H), 6.95 (d, J=11.3 Hz, 1H), 7.20-7.49 (m, 9H), 7.45(m, 1H), 7.52 (m, 1H), 8.05 (br s, 1H), 8.25 (m, 3H), 8.56 (m, 1H),10.95 (br s, 1H); t_(R)=6.73 min; MS (ion spray) 579.4 (M+1); Anal.Calc'd for C₃₁H₃₉FN₆O₄.2HCl.0.2CHCl3: C, 56.29; H, 6.24; N, 12.67.Found: C, 56.47; H, 6.17; N, 12.24.

Example 24. (Isomer 2) ¹H-NMR (d, DMSO) 0.75 (d, J=6.4 Hz, 1.5H), 0.88(d, J=6.4 Hz, 1.5H), 1.10 (m, 1H), 1.35 (m, 1H), 1.45-1.70 (m, 8H),2.60-2.75 (m, 2H), 3.15 (m, 1H), 3.65-3.85 (m, 3H), 4.35 (m, 1H), 4.52(s, 2H), 4.75 (m, 1H), 6.95 (d, J=11.3 Hz, 1H), 7.20-7.49 (m, 9H), 7.45(m, 1H), 7.52 (m, 1H), 8.05 (br s, 1H), 8.25 (m, 3H), 8.56 (m, 1H),10.95 (br s, 1H); t_(R)=9.09 min; MS (ion spray) 579.4 (M+1); Anal.Calc'd for C₃₁H₃₉FN₆O₄.2HCl: C, 57.14; H, 6.34; N, 12.90. Found: C,57.17; H, 6.18; N, 12.79.

Reaction of the product of Preparation 51 (0.6 g, 1.0 mmol), pyrrolidine(0.08 mL, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol) indimethylformamide (20 mL) as described in Preparation 6 gave 0.27 g(41%) of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (FD) 650.5 (M+); Anal. Calc'd for C₃₄H₄₃FN₆O₆.0.6H₂O: C,61.73; H, 6.73; N, 12.70. Found: C, 61.98; H, 6.43; N, 12.66.

Example 25

Reaction of the product of Preparation 53 (0.2 g, 0.3 mmol) andtrifluoroacetic acid (4 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.16 g (84%) of the desired mixture of isomers as ayellow solid: ¹H-NMR is consistent with structure. MS (high res) calc'dfor C₂₉H₃₆FN₆O₄: 551.2782. Found: 551.2790.

Reaction of the product of Preparation 51 (1.0 g, 1.7 mmol),dimethylamine hydrochloride (0.14 g, 1.7 mmol), triethylamine (0.26 mL,1.9 mmol), 1-hydroxybenzotriazole (0.26 g, 1.9 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol) indimethylformamide (30 mL) as described in Preparation 6 gave 0.55 g(52%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (ion spray) 625.4 (M+1); Anal. Calc'd for C₃₂H₄₁FN₆O₆: C,61.53; H, 6.61; N, 13.45. Found: C, 61.22; H, 6.33; N, 13.44.

Example 26

Reaction of the product of Preparation 54 (0.54 g, 0.86 mmol) andtrifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 1 gave 0.4 g (77%) of the desired product as a mixture ofisomers: ¹H-NMR is consistent with structure. MS (ion spray) 525.4(M+1); Anal. Calc'd for C₂₇H₃₃FN₆O₆.2HCl: C, 54.27; H, 5.90; N, 14.06.Found: C, 53.11; H, 5.70; N, 13.58.

Reaction of the product of Preparation 51 (0.6 g, 1.0 mmol),4-(4-fluorobenzoyl)piperidine hydrochloride (0.25 g, 1.0 mmol),triethylamine (0.16 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (40 mL) as described Preparation 6 gave 0.42g (53%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (ion spray) 787.4 (M+); Anal. Calc'd for C₄₂H₄₈F₂N₆O₇: C,63.83; H, 6.17; N, 10.63. Found: C, 63.95; H, 5.90; N, 10.44.

Example 27

Reaction of the product of Preparation 55 (0.4 g, 0.5 mmol) withtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.32 g (82%) of the desired product as a yellow foam:¹H-NMR is consistent with structure. MS (high res) calc'd forC₃₇H₄₁F₂N₆O₅: 687.3106. Found: 687.3103. Anal. Calc'd forC₃₇H₄₀F₂N₆O₅.2.4 HCl: C, 57.40; H, 5.52; N, 10.85. Found: C, 57.56; H,5.53; N, 10.50.

Reduction of the product of Preparation 4 (4.8 g, 16.0 mmol) with 10%palladium on carbon (5.0 g) and tetrahydrofuran (160 mL) followed bycoupling with the product of Preparation 1j (6.0 g, 16.0 mmol),1-hydroxybenzotriazole (2.4 g, 17.6 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.6 g, 17.6 mmol) asdescribed in Preparation 4 gave 15.4 g (77%) of the desired product as atan foam: 1H-NMR (d, DMSO) 1.17 (t, J=7.2 Hz, 3H), 1.23-1.45 (m, 15H),1.45-1.57 (m, 6H), 7.16 (q, J=6.8 Hz, 2H), 4.40 (m, 1H), 6.45 (s, 1H),7.05 (m, 1H), 7.10-7.30 (m, 8H), 7.40-7.48 (m, 3H), 7.54 (s, 1H), 10.20(br s, 1H); MS (ion spray) 624.4 (M+1); Anal. Calc'd for C₃₃H₄₂FN₅O₆: C,63.55; H, 6.79; N, 11.23. Found: C, 63.83; H, 6.78; N, 11.38.

Reaction of the product of Preparation 56 (14.8 g, 24.0 mmol) withlithium hydroxide (0.66 g, 29.0 mmol) in dioxane (200 mL) and water (100mL) as in described in Preparation 5 gave 14.3 g (100%) of the desiredproduct as a tan foam: ¹H-NMR (d, DMSO) 1.25-1.40 (m, 15H), 1.50-1.75(m, 6H), 4.40 (s, 1H), 6.60 (s, 1H), 7.05 (s, 1H), 7.10-7.30 (m, 8H),7.40-7.50 (m, 3H), 7.55 (s, 1H), 10.2 (br s, 1H), 13.63 (br s, 1H); MS(ion spray) 596.5 (M+1); Anal. Calc'd for C₃₁H₃₈FN₅O₆.0.1dioxane: C,62.39; H, 6.47; N, 11.59. Found: C, 62.16; H, 6.56; N, 11.28.

Reaction of the product of Preparation 57 (13.3 g, 23.1 mmol),4-methylpiperidine (3 mL, 23.1 mmol), 1-hydroxybenzotriazole (3.4 g,25.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.2 g,25.4 mmol) in dimethylformamide (100 mL) as described in Preparation 6gave 14.4 g (93%) of the desired product as a tan foam: ¹H-NMR (d, DMSO)0.76 (d, J=6.4 Hz, 1.5 H), 0.86 (d, J=4.9 Hz, 1.5H), 1.00 (m, 1H),1.25-1.45 (m, 17H), 1.45-1.75 (m, 8H), 2.60-2.80 (m, 2H), 3.75 (m, 1H),4.30-4.45 (m, 2H), 6.71 (d J=11.7 Hz, 1H), 7.05 (m, 1H), 7.10-7.30 (m,9H), 7.30-7.45 (m, 3H), 10.15 (m, 1H); MS (ion spray) 677.5 (M+1); Anal.Calc'd for C₃₇H₄₉FN₆O₅: C, 65.66; H, 7.30; N, 12.42. Found: C, 65.78; H,7.19; N, 12.44.

Example 28 and 29

Reaction of the product of Preparation 58 (13.8 g, 20.4 mmol) withtrifluoroacetic acid (16 mL) in dichloromethane (40 mL) as described inExample 1 gave 10.5 g (89%) of the desired mixture as a tan foam. Themixture (4.0 g) was purified by HPLC (8×15 cm Prochrom column packedwith Kromosil CHI-DMP chiral phase with an eluent mixture of 3A alcoholand dimethylethylamine in heptane) to give 1.5 g (38%) of isomer 1 and0.77 g (20%) of isomer 2 as white solids:

Example 28. (isomer 1) ¹H-NMR (d, DMSO) 0.75 (t, J=6.4 Hz, 1.5 H), 0.87(t, J=6.0 Hz, 1.5 H), 1.15 (m, 1H), 1.35 (m, 1H), 1.45-1.80 (m, 12H),2.55-2.75 (m, 3H), 3.05 (m, 1H), 3.65-3.75 (m, 2H), 4.30-4.50 (m, 2H),6.94 (d, J=12 Hz, 1H), 7.10-7.20 (m, 2H), 7.20-7.40 (m, 7H), 7.45 (m,1H), 7.55 (m, 1H), 8.08 (m, 1H), 8.15-8.30 (m, 3H), 8.44 (t, J=7.2 Hz,1H), 10.90 (br s, 1H); t_(R)=6.62 min; MS (ion spray) 578.3 (M+l); Anal.Calc'd for C₃₂H₄₁FN₆O₃.2.3HCl: C, 58.81; H, 6.61; N, 12.72. Found: C,57.91; H, 6.55; N, 12.72.

Example 29. (isomer 2) ¹H-NMR (d, DMSO) 0.75 (t, J=6.4 Hz, 1.5 H), 0.87(t, J=6.0 Hz, 1.5 H), 1.15 (m, 1H), 1.35 (m, 1H), 1.45-1.80 (m, 12H),2.55-2.75 (m, 3H), 3.05 (m, 1H), 3.65-3.75 (m, 2H), 4.30-4.50 (m, 2H),6.94 (d, J=12 Hz, 1H), 7.10-7.20 (m, 2H), 7.20-7.40 (m, 7H), 7.45 (m,1H), 7.55 (m, 1H), 8.08 (m, 1H), 8.15-8.30 (m, 3H), 8.44 (t, J=7.2 Hz,1H), 10.90 (br s, 1H); t_(R)=8.95 min; MS (ion spray) 578.3 (M+1); Anal.Calc'd for C₃₂H₄₁FN₆O₃.2.3HCl: C, 58.81; H, 6.61; N, 12.72. Found: C,58.05; H, 6.64; N, 12.43.

Reaction of 3,4-difluorophenylacetic acid (25.0 g, 145 mmol) withp-toluenesulfonic acid (9.5 g, 49.5 mmol) in absolute ethanol (150 mL)as described in Preparation 1 gave 28.7 g (99%) of the desired productas a colorless oil: ¹H-NMR is consistent with structure; MS (FD) 201(M+).

Reaction of the product of Preparation 59 (10.0 g, 50.0 mmol,N-bromosuccinimde (9.17 g, 51.5 mmol) and 48% HBr (4 drops) in carbontetrachloride (40 mL) as in Preparation 2 gave 12.0 g (86%) of thedesired product as a colorless oil which was used without furtherpurification: ¹H-NMR is consistent with structure; MS (ion spray) 278,280 (M+1).

Reaction of the product of Preparation 60 (10.5 g, 38 mmol),4-nitroimidazole (5.2 g, 45.6 mmol) and potassium carbonate (15.1 g, 114mmol) in dimethylformamide (400 mL) as described in Preparation 3 gave4.54 g (39%) of the desired product as an orange oil: ¹H-NMR isconsistent with structure; MS (ion spray) 312.0 (M+1); Anal. Calc'd forC₁₃H₁₁F₂N₃O₄.0.2H₂O: C, 49.59; H, 3.65; N, 13.35. Found: C, 49.58; H,3.62; N, 13.09.

Reduction of the product of Preparation 61 (1.35 g, 4.3 mmol) with 10%palladium on carbon (0.8 g) in tetrahydrofuran (40 mL) followed bycoupling with the product of Preparation 1d (1.64 g, 4.3 mmol),1-hydroxybenzotriazole (0.7 g, 4.7 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.04 g, 4.7 mmol) asdescribed in Preparation 4 gave 1.9 g (69%) of the desired product as atan foam: ¹H-NMR is consistent with structure; MS (ion spray) 644 (M+1);Anal. Calc'd for C₃₂H₃₉F₂N₅O₇: C, 59.71; H, 6.11; N, 10.80. Found: C,59.72; H, 6.04; N, 10.63.

Reaction of the product of preparation 62 (1.9 g, 3.0 mmol) with lithiumhydroxide (0.09 g, 3.6 mmol) in dioxane (50 mL) and water (25 mL) asdescribed in Preparation 5 gave 1.6 g (87%) of the desired product as atan foam: ¹H-NMR is consistent with structure; MS (ion spray) 616.4(M+1).

Reaction of the product of Preparation 63 (0.5 g, 0.8 mmol),4-methylpiperidine (0.1 mL, 0.8 mmol), 1-hydroxybenzotriazole (0.12 g,0.88 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.18 g,0.88 mmol) in dimethylformamide (40 mL) as described in Preparation 6gave 0.3 g (54%) of the desired product as a white foam: ¹H-NMR isconsistent with structure; MS (ion spray) 697 (M+1); Anal. Calc'd forC₃₆H₄₆F₂N₆O₆; C, 62.06; H, 6.65; N, 12.06. Found: C, 61.82; H, 6.57; N,11.96.

Example 30

Reaction of the product of Preparation 64 (0.22 g, 0.3 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.2 g (100%) of the desired mixture of isomers as ayellow foam: ¹H-NMR is consistent with structure; MS (ion spray) 597.5(M+1); Anal. Calc'd for C₃₁H₃₈F₂N₆O₄.2.2HCl; C, 55.01; H, 5.99; N,12.42. Found: C, 55.16; H, 5.96; N, 12.20.

Reaction of the product of Preparation 63 (0.5 g, 0.8 mmol), pyrrolidine(0.07 mL, 0.8 mmol), 1-hydroxybenzotriazole (0.12 mL, 0.88 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.18 g, 0.88 mmol) indimethylformamide (40 mL) as described in Preparation 6 gave 0.25 g(42%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure. MS (ion spray) 669.4 (M+1); Anal. Calc'd forC₃₄H₄₂F₂N₆O₆.0.7H₂O: C, 59.94; H, 6.42; N, 12.33. Found: C, 59.96; H,6.28; N, 11.97.

Example 31

Reaction of the product of Preparation 65 (0.2 g, 0.3 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.14 g (74%) of the desired product as a yellow foam:¹H-NMR is consistent with structure; MS (ion spray) 569.4 (M+1); Anal.Calc'd for C₂₉H₃₄F₂N₆O₄.2.2HCl: C, 53.68; H, 5.62; N, 12.95. Found: C,53.83; H, 5.57; N, 12.37.

Reaction of the product of preparation 63 (0.5 g, 0.8 mmol),4-(4-fluorobenzoyl)piperidine hydrochloride (0.2 g, 0.8 mmol),triethylamine (0.13 mL, 0.88 mmol), 1-hydroxybenzotriazole (0.12 g, 0.88mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.18 g, 0.88mmol) in dimethylformamide (40 mL) as described in Preparation 5 gave0.14 g (22%) of the desired product as a white foam: ¹H-NMR isconsistent with structure; MS (ion spray) 805.6 (M+1); Anal. Calc'd forC₄₂H₄₇F₃N₆O₇: C, 62.68; H, 5.89; N, 10.44. Found: C, 62.45; H, 5.82; N,10.40.

Example 32

Reaction of the product of Preparation 66 (0.14 g, 0.17 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.1 g (77%) of the desired mixture of isomers as a yellowsolid: ¹H-NMR is consistent with structure; MS (ion spray) 705.5 (M+1);Anal. Calc'd for C₃₇H₃₉F₃N₆O₅.2.1HCl: C, 56.88; H, 5.30; N, 10.76.Found: C, 56.64; H, 5.31; N, 10.30.

Reaction of 2,4-difluorophenylacetic acid (20 g, 116 mmol) andp-toluenesulfonic acid (6.0 g, 31 mmol) in absolute ethanol (150 mL) asdescribed in Preparation 1 gave 22.1 g (95%) of the desired product as acolorless oil which solidifies upon setting: ¹H-NMR is consistent withstructure; MS (FD) 200 (M+).

Preparation 68

Reaction of the product of Preparation 67 (21.4 g, 100 mmol),N-bromosuccinimide (19.6 g, 103 mmol) and 48% HBr (6 drops) in carbontetrachloride (100 mL) as described in Preparation 2 gave 27.9 g (100%)of the desired product as a colorless oil: ¹H-NMR is consistent withstructure; MS (FD) 278, 280 (M+); Anal. Calc'd for C₁₀H₉BrF₂O₂: C,43.04; H, 3.25. Found: C, 42.92; H, 3.15.

Reaction of the product of Preparation 68 (26.9 g, 96 mmol),4-nitroimidazole (13.0 g, 115 mmol) and potassium carbonate (40 g, 288mmol) in dimethylformamide (150 mL) as described in Preparation 3 gave14.3 g (48%) of the desired product as an orange oil: ¹H-NMR isconsistent with structure; MS (ion spray) 312 (M+1); Anal. Calc'd forC₁₃H₁₁F₂N₃O₄: C, 50.17; H, 3.56; N, 13.50. Found: C, 49.90; H, 3.56; N,13.26.

Reduction of the product of preparation 69 (1.35 g, 4.3 mmol) with 10%palladium on carbon (0.8 g) in tetrahydrofuran (40 mL) followed bycoupling with the product of Preparation 1d (1.64 g, 4.3 mmol),1-hydroxybenzotriazole (0.7 g, 4.7 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.04 g, 4.7 mmol) asdescribed in Preparation 4 gave 1.52 g (55%) of the desired product as atan foam: ¹H-NMR is consistent with structure; MS (ion spray) 644.5(M+1); Anal. Calc'd for C₃₂H₃₉F₂N₅O₇: C, 59.71; H, 6.11; N, 10.88.Found: C, 59.43; H, 5.97; N, 10.91.

Reaction of the product of preparation 70 (1.42 g, 2.2 mmol) withlithium hydroxide (0.07 g, 2.64 mmol) in dioxane (50 mL) and water (25mL) as described in Preparation 5 gave 1.35 g (100%) of the desiredproduct as a tan foam: ¹H-NMR is consistent with structure; MS (ionspray) 616.3 (M+1); Anal. Calc.d for C₃₀H₃₅F₂N₅O₇; C, 58.33; H, 5.73; N,11.38. Found: C, 57.71; H, 5.86; N, 10.80.

Reaction of the product of Preparation 71 (0.6 g, 1.0 mmol),4-methylpiperidine (0.12 mL, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g,1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (30 mL) as described in Preparation 6 gave0.66 g (94%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 696 (M+); Anal. Calc'd for C₃₆H₄₆F₂N₆O₆: C,62.05; H, 6.65; N, 12.06. Found: C, 62.21; H, 6.48; N, 12.17.

Example 33

Reaction of the product of Preparation 72 (0.51 g, 0.73 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as in described inExample 1 gave 0.25 g (51%) of the desired product as tan foam: ¹H-NMRis consistent with structure; MS (ion spray) 597.5 (M+1); Anal. Calc'dfor C₃₁H₃₈F₂N₆O₄.2.2HCl: C, 55.01; H, 5.99; H, 12.42. Found: C, 56.92;H, 5.98; N, 12.36.

Reaction of the product of Preparation 71 (0.6 g, 1.0 mmol), pyrrolidine(0.8 mL, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol);dimethylformamide (30 mL) as described in Preparation 6 gave 0.4 g (58%)of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (ion spray) 669.5 (M+1); Anal. Calc'd for C₃₂H₄₂F₂N₆O₆: C,61.07; H, 6.33; N, 12.57. Found: C, 60.84; H, 6.31; N, 12.32.

Example 34

Reaction of the product of Preparation 73 (0.3 g, 0.45 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.21 g (70%) of the desired product as a white foam:¹H-NMR is consistent with structure; MS (ion spray) 569.4 (M+1); Anal.Calc'd for C₂₉H₃₄F₂N₆O₄.2.3HCl: C, 53.38; H, 5.61; N, 12.88. Found: C,53.59; H, 5.58; N, 12.42.

To a solution of the compound of Preparation 49 (17.0 g, 58.0 mmol)stirring at room temperature was added to sodium hydroxide (125 mL of a2N aqueous solution) along with tetrahydrofuran (10 mL) and ethanol (10mL). After hydrolysis was complete, the mixture was cooled in an bathand acidified to pH 2.75 with aqueous hydrochloric acid and extractedwith ethyl acetate. The combined organic extracts were washed withwater, dried over sodium sulfate and concentrated to provide 15.0 g(99%) of the desired carboxylic acid. The crude material was combinedwith aqueous N,N-dimethyl amine (40%, 9.0 mL, 71.8 mmol),1-hydroxybenzotriazole hydrate (7.64 g, 56.6 mmol) and1,3-dicyclohexylcarbodiimide (11.7 g, 56.6 mmol) in tetrahydrofuran (150mL). After 18 h, the mixture was concentrated and the residue slurriedin ethyl acetate, filtered, and the filtrate concentrated. Purificationof the concentrate by flash chromatography (silica gel,chloroform/methanol) provided 10.2 g (62%) of the desired product: ESMS:(M+H)⁺ 293.1. ¹H NMR (300 MHz, DMSO-d₆) δ8.21 (d, 1H, J=1.51 Hz) 7.80(d,1H, J=1.13 Hz), 7.60-7.50 (m, 2H,), 7.38-7.25 (m, 2H), 6.88 (s, 1H),2.92 (s, 3H), 2.86 (s, 3H). Anal. Calcd. for C₁₃H₁₃N₄O₃: C, 53.43; H,4.48; N, 19.17. Found: C, 53.43; H, 4.71; N, 19.07.

The product of Preparation 74 (2.0 g (6.85 mmol) was combined with 10%palladium/carbon (1.80 g) and palladium/black (0.20 g) intetrahydrofuran(75 mL) and the mixture shaken under a hydrogenatmosphere (38 mm Hg) in a Parr apparatus. After reduction was complete,the catalyst was removed by filtration through celite and the resultingsolution was immediately added to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.51 g, 7.3 mmol),1-hydroxybenzotriazole (1.0 g, 7.3 mmol), the product of Preparation 1j(2.77 g, 7.3 mmol) in tetrahydrofuran (50 mL) at room temperature. After16 h, the mixture was concentrated and the residue slurried in ethylacetate then filtered. The filtrate was concentrated and resulting crudeproduct purified by flash chromatography (silica gel,chloroform/methanol) which afforded 3.47 g (81%) of the desired product:ESMS: (M+H)⁺ 623.5, 624.6. ¹H NMR was consistent with product. Anal.Calcd. for C₃₃H₄₃N₆O₄F.0.02 CHCl3: C, 63.44; H, 6.94; N, 13.44. Found:C, 63.04; H, 7.41; N, 11.93.

Example 35

To a solution of the product of Preparation 75 (1.45 g, 2.29 mmol)stirring at room temperature in dichloromethane (50 mL) was addedtriflouroacetic acid (15 mL). After 3 hours, the mixture wasconcentrated and the material treated with excess aqueous sodiumbicarbonate. The aqueous mixture was extracted with ethyl acetate andthe combined organic extracts concentrate. The resulting residue waspurified by flash chromatography (silica gel, chloroform/methanol) toprovide 1.55 g of the desired product: ESMS: (M+H)⁺ 523.3. The isomericmixture (3.44 g) was separated as previously described in Example 7 toprovide 0.98 g of pure isomer 1 (t_(R)=7.94 min) and 0.81 g of isomer 2(t_(R)=10.57 min). For isomer 2, 0.80 g (1.53 mmol) was dissolved inethyl acetate/methanol and treated with a saturated solution ofhydrochloric acid in diethyl ether. The resulting mixture wasconcentrated to provide 0.90 g (92%) of the desired product as a lighttan solid: ESMS: (M+H)⁺ 523.4, 524.5. ¹H NMR was consistent withproduct. Anal. Calcd. for C₂₈H₃₅N₆O₃F.3.25 HCl: C, 52.46; H, 6.01; N,13.11. Found: C, 52.49; H, 6.23; N, 11.80.

The product of Preparation 74 (2.00 g, 6.85 mmol) was combined with 10%palladium/carbon (1.80 g) and palladium/black (0.20 g) intetrahydrofuran 75 mL) and the mixture shaken under hydrogen atmosphere(39 mm Hg) in a Parr apparatus. After reduction was complete, thecatalyst was removed by filtration through celite and theamine/tetrahydrofuran solution was immediately combined with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(1.41 g, 6.85 mmol),1-hydroxybenzotriazole mono-hydrate (0.93 g, 6.85 mmol), the product ofPreparation 1j (2.60 g, 6.84 mmol) and additional tetrahydrofuran (75mL). After stirring overnight at ambient temperature, the mixture wasconcentrated and the residue slurried in ethyl acetate. The filtrate wasconcentrated and the residue purified by flash chromatography (silicagel, chloroform/methanol) to provide 3.65 g (85%) of the desired productas a tan solid: ESMS: (M+H)⁺ 625.4. ¹H NMR was consistent with product.Anal. Calcd. for C₃₂H₄₁N₆O₆.0.03 chloroform: C, 61.17; H, 6.60; N,13.34. Found: C, 61.25; H, 6.90; N, 12.69.

Example 36

To a solution of the product of Preparation 75 (3.30 g, 5.3 mmol)stirring in dichloromethane (30 mL) at room temperature was addedtriflouroacetic acid (10 m). After 3 h, the mixture was concentrated andthe residue treated with excess aqueous sodium bicarbonate. Theresulting mixture was extracted with ethyl acetate and the combinedorganic extracts were washed with 1N aqueous sodium hydroxide, driedover sodium sulfate, and concentrated. The residue was purified by flashchromatography (silica gel, chloroform/methanol) to provide 1.40 g (51%)of the desired product as a light tan solid: ESMS: (M+H)⁺ 525.3. ¹H NMRwas consistent with product. Anal. Calcd. for C₂₇H₃₃N₆O₄F.1.3 methanol:C, 60.03; H, 6.80; N, 14.84. Found: C, 60.19; H, 6.81; N, 14.56. Theisomeric mixture (3.20 g) was separated as previously described inExample 7 to give 1.57 g of isomer 1 (t_(R)=7.57 min) and 0.88 g ofisomer 2 (t_(R)=10.43 min). For isomer 2, 0.88 g (1.68 mmol) wasdissolved in ethyl acetate and treated with a saturated solution ofhydrochloric acid in diethyl ether. The resulting mixture wasconcentrated, washed with diethyl ether to give 0.97 g of the desiredproduct: ESMS: (M+H)⁺ 525.4, 526.7. ¹H NMR was consistent with product.Anal. Calcd. for C₂₅H₃₃N₆O₄F.2.75 HCl: C, 51.73; H, 6.07; N, 13.41.Found: C, 51.62; H, 5.74; N, 13.34.

Reaction of 4-ethoxyphenylacetic acid (23.5 g, 130 mmol) andp-toluenesulfonic acid (4.0 g, 21 mmol) in absolute ethanol (150 mL) asdescribed in Preparation 1 gave 23.2 g (86%) of the desired product as acolorless oil: ¹H-NMR (d, DMSO) 1.17 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2Hz, 3H), 3.56 (s, 2H), 3.99 (q, J=7.2 Hz, 2H), 4.05 (q, J=7.2 Hz, 2H),6.85 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H); MS (ion spray) 209(M+1); Anal. Calc'd for C₁₂H₁₆O₃: C, 69.21; H, 7.74. Found: C, 68.91; H,7.55.

To a solution of the product of Preparation 76 (53 g, 255 mmol) stirringin carbon tetrachloride (600 mL) at room temperature was added 46.6 g(262 mmol) of N-bromosuccinimide and 3.0 g (18.3 mmol) of2,2′-azobis(2-methylpropionitrile). The resulting reaction mixture washeated to reflux. After 3.5 h, the solution was cooled to roomtemperature, filtered and concentrated. The resulting oil waschromatographed on silica gel using chloroform as eluant to afford 70.9g (97%) of the desired product as a colorless oil: ¹H-NMR (d, DMSO) 1.17(t, J=7.2 Hz, 3H), 1.25-1.35 (m, 3H), 4.00-4.10 (m, 2H), 4.13-4.25 (m,2H), 5.86 (s, 1H), 6.92 (d, J=8.7 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H); MS(FD) 287, 289 (M+).

Reaction of the product of Preparation 77 (11.4 g, 40 mmol),4-nitroimidazole (4.5 g, 40 mmol) and potassium carbonate (16.6 g, 120mmol) in dimethylformamide (100 mL) as described in Preparation 3 gave5.47 g (43%) of the desired product as a yellow oil: ¹H-NMR (d, DMSO)1.18 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 4.03 (q, J=7.2 Hz, 2H),4.23 (q, J=7.2 Hz, 2H), 6.54 (s, 1H), 6.70 (d, J=8.7 Hz, 2H), 7.42 (d,J=8.7 Hz, 2H), 7.90 (s, 1H), 8.34 (s, 1H); MS (ion spray) 320.2 (M+1);Anal. Calc'd for C₁₅H₁₇N₃O₅: C, 56.42; H, 5.37; N, 13.16. Found: C,56.29; H, 5.17; N, 13.15.

Reduction of the product of Preparation 78 (9.6 g, 30 mmol) with 10%palladium on carbon (7.0 g) in tetrahydrofuran (100 mL) followed bycoupling with the product of Preparation 1d (11.5 g, 30 mmol),1-hydroxybenzotriazole (4.5 g, 33 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (6.8 g, 33 mmol) asdescribed in Preparation 4 gave 9.9 g (50%) of the desired product as atan foam: ¹H-NMR (d, DMSO) 1.17 (t, J=7.2 Hz, 3H), 1.25-1.40 (m, 18H),3.58 (m, 1H), 3.70 (m, 1H), 4.02 (q, J=7.2 Hz, 2H), 4.20 (q, J=7.2 Hz,2H), 4.44 (d, J=3.4 Hz, 2H), 4.60 (m, 1H), 6.33 (s, 1H), 6.95 (d, J=8.7Hz, 2H), 7.15-7.35 (m, 9H), 7.43 (m, 1H), 7.51 (m, 1H), 10.2 (br s, 1H);MS (ion spray) 652.4 (M+1); Anal. Calc'd for C₃₄H₄₅N₅O₈: C, 62.66; H,6.96; N, 10.74. Found: C, 62.92; H, 7.00; N, 10.98.

Reaction of the product of Preparation 80 (9.7 g, 15.0 mmol) and lithiumhydroxide (0.42 g, 18.0 mmol) in dioxane (200 mL) and water (100 mL) asdescribed in Preparation 5 gave 9.4 g (100%) of the desired product as atan foam: ¹H-NMR (d, DMSO) 1.25-1.40 (m, 18H), 3.60 (m, 1H), 3.68 (m,1H), 4.02 (q, J=7.2 Hz, 2H), 4.44 (d, J=3.0 Hz, 2H), 4.60 (m, 1H), 6.19(m, 1H), 6.95 (d, J=8.7 Hz, 2H), 7.28-7.35 (m, 9H), 7.40 (m, 1H), 7.51(s, 1H), 10.2 (br s, 1H), 13.5 (br s, 1H); MS (ion spray) 624.5 (M+1);Anal. Calc'd for C₄₃H₄₁N₅O₈: C, 61.62; H, 6.63; N, 11.23. Found: C,61.58; H, 6.92; N, 10.99.

Reaction of the product of Preparation 80 (7.43 g, 12.0 mmol),4-methylpiperidine (1.42 mL, 12.0 mmol), 1-hydroxybenzotriazole (1.78 g,13.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.72 g,13.2 mmol) in dimethylformamide (100 mL) as described in Preparation 6gave 6.4 g (76%) of the desired product as a tan foam: ¹H-NMR (d, DMSO)0.74 (d, J=6.4 Hz, 1.5 H), 0.87 (d, J=6.0 Hz, 1.5H), 1.05 (m, 1H),1.25-1.40 (m, 18H), 1.50-1.70 (m, 3H), 2.55-2.70 (m, 2H), 3.00 (m, 1H),3.57 (m, 1H), 3.65-3.85 (m, 2H), 4.00-4.20 (m, 2H), 4.38 (m, 1H), 4.44(d, J=3.4 Hz, 2H), 4.60 (m, 1H), 6.61 (d, J=12.0 Hz, 1H), 6.95-7.00 (m,2H), 7.15-7.20 (m, 2H), 7.20-7.45 (m, 9H), 10.15 (br s, 1H); MS (ionspray) 705.5 (M+1); Anal. Calc'd for C₃₈H₅₂N₆O₇: C, 64.75; H, 7.44; N,11.92. Found: C, 64.59; H, 7.21; N, 11.87.

Examples 37 and 38

Reaction of the product of Preparation 81 (6.4, 9.1 mmol) andtrifluoroacetic acid (10 mL) in dichloromethane (25 mL) as described inExample 1 gave 4.71 g (77%) of the desired mixture of diastereomers as atan foam. Resolution of the diastereomers (2.4 g) by HPLC (KromsilCHI-DMP chiral stationary phase, 3A alcohol/dimethylethylamine/heptane)provided 200 mg (8%) of isomer 1 and 0.8 g (31%) of isomer 2, bothisolated as white solids after acidification with hydrochloric acid asdescribed in Example 7:

Example 37. (Isomer 1) ¹H-NMR (d, DMSO) 0.74 (d, J=6.4 Hz, 1.5H), 0.88(d, J=6.0 Hz, 1.5H), 1.20 (m, 1H), 1.31 (t, J=6.8 Hz, 3H), 1.45-1.70 (m,8H), 2.60-2.70 (m, 2H), 3.05 (m, 1H), 3.65-3.80 (m, 3H), 4.00-4.20 (m,3H), 4.37 (m, 1H), 4.52 (s, 2H), 4.75 (m, 1H), 6.80 (d, J=13.2 Hz, 1H),6.95-7.05 (m, 2H), 7.25-7.40 (m, 9H), 7.92 (br s, 1H), 8.20-8.30 (m,3H), 8.53 (d, J=7.2 Hz, 1H), 10.9 (br s, 1H); t_(R)=9.17 min; MS (ionspray) 605 (M+1); Anal. Calc'd for C₃₃H₄₄N₆O₅.2HCl.0.1 CHCl3: C, 58.45;H, 6.74; N, 12.74. Found: C, 58.64; H, 6.77; N, 12.36.

Example 38. (Isomer 2) ¹H-NMR (d, DMSO) 0.74 (d, J=6.4 Hz, 1.5H), 0.88(d, J=6.0 Hz, 1.5H), 1.20 (m, 1H), 1.31 (t, J=6.8 Hz, 3H), 1.45-1.70 (m,8H), 2.60-2.70 (m, 2H), 3.05 (m, 1H), 3.65-3.80 (m, 3H), 4.00-4.20 (m,3H), 4.37 (m, 1H), 4.52 (s, 2H), 4.75 (m, 1H), 6.80 (d, J=13.2 Hz, 1H),6.95-7.05 (m, 2H), 7.25-7.40 (m, 9H), 7.92 (br s, 1H), 8.20-8.30 (m,3H), 8.53 (d, J=7.2 Hz, 1H), 10.9 (br s, 1H); t_(R)=12.68 min; MS (ionspray) 605 (M+1); Anal. Calc'd for C₃₃H₄₄N₆O₅.HCl: C, 59.35; H, 6.85; N,12.98. Found: C, 59.62; H, 7.01; N, 12.71.

Reaction of the product of Preparation 80 (0.9 g, 1.5 mmol),dimethylamine hydrochloride (0.13 g, 1.5 mmol), triethylamine (0.23 mL,1.65 mmol), 1-hydroxybenzotriazole (0.23 g, 1.65 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.34 g, 1.65 mmol) indimethylformamide (50 mL) as described in Preparation 6 gave 0.46 g(47%) of the desired product as a tan foam: ¹H-NMR (d, DMSO) 1.25-1.35(m, 18H), 2.90 (m, 6H), 3.57 (m, 1H), 3.67 (m, 1H), 4.03 (q, J=7.2 Hz,2H), 4.43-4.47 (m, 2H), 4.57 (m, 1H), 6.55 (m, 1H), 6.97 (d, J=8.7 Hz,2H), 7.15-7.45 (m, 11H), 10.16 (br s, 1H); MS (ion spray) 651.4 (M+1);Anal. Calc'd for C₃₄H₄₆N₆O₇: C, 62.75; H, 7.13; N, 12.91. Found: C,62.55; H, 6.84; N, 12.84.

Examples 39 and 40

Reaction of the product of Preparation 82 (0.44 g, 0.68 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.19 g (45%) of the desired product as a tan foam.Resolution of the diastereomers (90 mg, 0.14 mmol) by HPLC (KromsilCHI-DMP chiral stationary phase, 3A alcohol/dimethylethylamine/heptane)provided 50 mg (50%) of isomer 1 and 27 mg (27%) of isomer 2, bothisolated as white solids after acidification with hydrochloric acid asdescribed in Example 7:

Example 39. (isomer 1): ¹H-NMR (d, DMSO) 1.32 (t, J=6.8 Hz, 3H), 1.50(s, 6H), 2.86 (s, 3H), 2.90 (s, 3H), 3.70-3.80 (m, 2H), 4.03 (q, J=7.2Hz, 2H), 4.52 (s, 2H), 4.75 (m, 1H), 6.76 (s, 1H), 7.00 (d, J=8.7 Hz,2H), 7.25-7.40 (m, 9H), 8.06 (m, 1H), 8.20-8.30 (m, 3H), 8.52-8.60 (m,1H), 11.00 (br s, 1H); t_(R)=7.70 min; MS (high res) calc'd forC₂₉H₃₉N₆O₅: 551.2982. Found: 551.2987. Anal. Calc'd for C₂₉H₃₈N₆O₅.2.3HCl.0.3ethyl acetate: C, 54.88; H, 6.51; N, 12.72. Found: C, 54.70; H,6.49; N, 12.43.

Example 40. (isomer 2): ¹H-NMR (d, DMSO) 1.32 (t, J=6.8 Hz, 3H), 1.50(s, 6H), 2.86 (s, 3H), 2.90 (s, 3H), 3.70-3.80 (m, 2H), 4.03 (q, J=7.2Hz, 2H), 4.52 (s, 2H), 4.75 (m, 1H), 6.76 (s, 1H), 7.00 (d, J=8.7 Hz,2H), 7.25-7.40 (m, 9H), 8.06 (m, 1H), 8.20-8.30 (m, 3H), 8.52-8.60 (m,1H), 11.00 (br s, 1H); t_(R)=9.09 min; MS (high res) calc'd forC₂₉H₃₉N₆O₅: 551.2982. Found: 551.2976. Anal. Calc'd forC₂₉H₃₈N₆O₅.2.HCl.0.3 ethyl acetate: C, 55.18; H, 6.53; N, 12.79. Found:C, 55.01; H, 6.33; N, 12.54.

Reaction of the product of Preparation 80 (0.9 g, 1.5 mmol), pyrrolidine(0.13 mL, 1.5 mmol), 1-hydroxybenzotriazole (0.23 g, 1.65 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.34 g, 1.65 mmol) indimethylformamide (40 mL) as described in Preparation 6 gave 0.7 g (74%)of the desired product as a tan foam: ¹H-NMR (d, DMSO) 1.25-1.40 (m,18H), 1.70-1.90 (m, 4H), 2.95 (m, 1H), 3.30-3.40 (m, 2H), 3.55-3.70 (m,3H), 4.03 (q, J=7.2 Hz, 2H), 4.44 (d, J=3.4 Hz, 2H), 4.57 (m, 1H), 6.34(s, 1H), 6.97 (d, J=8.7 Hz, 2H), 7.20-7.35 (m, 9H), 7.40-7.45 (m, 2H),10.15 (br s, 1H); MS (ion spray) 677.6 (M+1); Anal. Calc'd forC₃₆H₄₈N₆O₇.0.0.2H₂0: C, 63.55; H, 7.17; N, 12.35. Found: C, 63.32; H,6.96; N, 12.24.

Example 41

Reaction of the product of Preparation 83 (0.59 g, 0.9 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.36 g (64%) of the desired product as a mixture ofisomers: ¹H-NMR (d, DMSO) 1.32 (t, J=6.8 Hz, 3H), 1.45-1.60 (m, 6H),1.65-1.90 (m, 4H), 2.90 (m, 1H), 3.25-3.45 (m, 2H), 3.65-3.75 (m, 3H),4.02 (q, J=6.8 Hz, 2H), 4.45-4.55 (m, 2H), 4.70-4.80 (m, 1H), 6.54 (s,1H), 6.98 (d, J=8.7 Hz, 2H), 7.20-7.40 (m, 9H), 8.05 (m, 1H), 8.20-8.30(m, 3H), 8.54 (d, J=7.2 Hz, 1H), 10.95 (br s, 1H); MS (high res) calc'dfor C₃₁H₄₁N₆O₅: 577.3138. Found: 577.3132. Anal. Calc'd forC₃₁H₄₀N₆O₅.2HCl: C, 57.32; H, 6.52; N, 12.94. Found: C, 57.46; H, 6.59;N, 12.91.

Reaction of 4-butyloxyphenylacetic acid (10.0 g, 48 mmol) andp-toluenesulfonic acid (2.5 g, 13 mmol) in absolute ethanol (100 mL) asdescribed in Preparation 1 gave 11.04 g (98%) of the desired product asa colorless oil: ¹H-NMR (d, DMSO) 0.94 (t, J=7.4 Hz, 3H), 1.18 (t, J=7.0Hz, 3H), 1.40-1.50 (m, 2H), 1.60-1.80 (m, 2H), 3.57 (s, 2H), 3.93 (q,J=6.5 Hz, 2H), 4.08 (q, J=7.3 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 7.15 (d,J=8.4 Hz, 2H); MS (ion spray) 237 (M+1) ; Anal. Calc'd for C₁₄H₂₀O₃: C,71.16; H, 8.53. Found: C, 71.33; H, 8.55.

To a solution of the product of Preparation 84, 6.0 g (25 mmol) in 100mL of carbon tetrachloride was added 4.7 g (25.8 mmol) ofN-bromosuccinimide and 0.6 g of 2,2′-azobis(2-methylpropionitrile). Thereaction mixture was heated to reflux. After 3.5 h, the mixture wascooled to room temperature, filtered and concentrated. The resulting oilwas purified by flash chromatography (silica gel, 3%methanol/chloroform) to proved 6.9 g (88%) of the desired product as acolorless oil: ¹H-NMR (d, DMSO) 0.93 (t, J=7.35 H, 3H), 1.20 (t, J=7.2Hz, 3H), 1.40-1.50 (m, 2H), 1.60-1.80 (m, 2H), 3.95-4.05 (m, 2H),4.10-4.15 (m, 2H), 5.87 (s, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7Hz, 2H); MS (FD) 314, 316 (M+); Anal. Calc'd for C₁₄H₁₉BrO₃.0.5CHCl₃: C,52.54; H, 5.98. Found: C, 52.35; H, 5.84.

Reaction of the product of Preparation 85(5.82 g, 19.0 mmol),4-nitroimidazole (2.1 g, 19.0 mmol) and potassium carbonate (8.0 g, 57mmol) in dimethylformamide (150 mL) as described in Preparation 3 gave3.5 g (53%) of the desired product as a yellow oil: ¹H-NMR (d, DMSO)0.93 (t, J=7.3 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H), 1.35-1.50 (m, 2H),1.60-1.80 (m, 2H), 3.92-4.06 (m, 2H), 4.20-4.30 (m, 2H), 6.56 (s, 1H),6.99 (d, J=8.6 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.92 (s, 1H), 8.37 (s,1H); MS (ion spray) 348.3 (M+1); Anal. Calc'd for C₁₇H₂₁N₃O₅: C, 58.78;H, 6.09; N, 12.10. Found: C, 59.08; H, 6.21; N, 12.19.

Reduction of the product of Preparation 86 (1.5 g, 4.3 mmol) with 10%palladium on carbon (0.8 g) in tetrahydrofuran (40 mL) followed bycoupling with the product of Preparation 1d (1.64 g, 4.3 mmol),1-hydroxybenzotriazole (0.7 g, 4.7 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.04 g, 4.7 mmol) asdescribed in Preparation 4 gave 1.1 g (38%) of the desired product as atan foam: ¹H-NMR (d, DMSO) 0.92 (t, J=7.5 Hz, 3H), 1.18 (t, J=7.2 Hz,3H), 1.25-1.40 (m, 15H), 1.40-1.50 (m, 2H), 1.60-1.75 (m, 2H), 3.60 (m,1H), 3.70 (m, 1H), 3.95-4.00 (m, 2H), 4.20-4.25 (m, 2H), 4.45-4.48 (m,2H), 4.57 (m, 1H), 6.35 (s, 1H), 6.97 (t, J=9.0 Hz, 2H), 7.15-7.35 (m,9H), 7.40 (m, 1H), 7.50 (s, 1H), 10.20 (br s, 1H); MS (ion spray) 680.5(M+1); Anal. Calc'd for C₃₆H₄₉N₅O₈: C, 63.61; H, 7.27; N, 10.30. Found:C, 63.53; H, 6.99; N, 10.54.

Reaction of the product of Preparation 87 (1.1 g, 1.6 mmol) and lithiumhydroxide (0.5 g, 1.92 mmol) in dioxane (50 mL) and water (25 mL) asdescribed in Preparation 5 gave 1.04 g (100%) of the desired product asa tan foam: ¹H-NMR (d, DMSO) 0.95 (t, J=7.5 Hz, 3H), 1.25-1.35 (m, 15H),1.35-1.50 (m, 2H), 1.65-1.75 (m, 2H), 3.57 (m, 1H), 3.65 (m, 1H), 3.95(t, J=6.4 Hz, 2H), 4.57 (m, 1H), 6.19 (d, J=1.5 Hz, 2H), 6.20 (s, 1H),6.96 (d, J=8.7 Hz, 2H), 7.10-7.35 (m, 9H), 7.40 (m, 1H), 7.50 (s, 1H),10.20 (br s, 1H), 13.45 (br s, 1H); MS (ion spray) 652.5 (M+1); Anal.Calc'd for C₃₂H₄₅N₅O₈: C. 62.66; H, 6.96; N, 10.75. Found: C, 62.45; H,7.07; N, 10.72.

Reaction of the product of Preparation 88 (1.0 g, 1.6 mmol),4-methylpiperidine (0.19 mL, 1.6 mmol), 1-hydroxybenzotriazole (0.24 g,1.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.35 g, 1.8mmol) in dimethylformamide (60 mL) as described in Preparation 6 gave0.57 g (48%) of the desired product as a tan foam: ¹H-NMR (d, DMSO) 0.75(d, J=6.0 Hz, 1H), 0.85-0.95 (m, 6H), 1.25-1.40 (m, 15H), 1.40-1.75 (m,7H), 2.55-2.75 (m, 2H), 3.00 (m, 1H), 3.55 (m, 1H), 3.60-3.85 (m, 2H),3.95-4.00 (m, 2H), 4.60 (m, 1H), 4.85-4.98 (m, 3H), 6.97 (d, J=8.7 Hz,1H), 6.90-7.00 (m, 2H), 7.15 (m, 1H), 7.20-7.45 (m, 10H), 10.15 (br s,1H); MS (ion spray) 733.5 (M+1); Anal. Calc'd for C₄₀H₅₆N₆O₇: C, 65.55;H, 7.70; N, 11.47. Found: C, 65.44; H, 7.49; N, 11.59.

Examples 42 and 43

Reaction of the product of Preparation 89 (0.55 g, 0.75 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.4 g (75%) of the desired product as a mixturediastereomers. This material was resolved by HPLC (Kromsil CHI-DMPchiral stationary phase, 3A alcohol/dimethylethylamine/heptane) toprovide the desired diastereomers, both isolated as white solids afteracidification with hydrochloric acid as described in Example 7:

Example 42. (isomer 1): ¹H-NMR (d, DMSO) 0.75 (d, J=6.4 Hz, 1H),0.85-1.00 (m, 5H), 1.25-1.40 (m, 2H), 1.40-1.50 (m, 2H), 1.50-1.60 (m,6H), 1.60-1.75 (m, 4H), 2.60=2.70 (m, 2H), 3.00 (m, 1H), 3.60-3.75 (m,3H), 3.95-4.00 (m, 2H), 4.52 (s, 2H), 4.75 (m, 1H), 4.88 (m, 1H), 6.89(d, J=14 Hz, 1H), 7.00-7.05 (m, 2H), 7.20-7.40 (m, 9H), 8.10 (m, 1H),8.20-8.30 (m, 3H), 8.60 (m, 1H), 11.02 (br s, 1H); t_(R)=5.90 min; MS(high res) calc'd for C₃₅H₄₉N₆O₅: 633.3764. Found: 633.3768. Anal.Calc'd for C₃₅H₄₈N₆O₅.2.3HCl: C, 58.66; H, 7.07; N, 11.73. Found: C,58.59; H, 6.99; N, 11.46.

Example 43. (isomer 2): ¹H-NMR (d, DMSO) 0.75 (d, J=6.4 Hz, 1H),0.85-1.00 (m, 5H), 1.25-1.40 (m, 2H), 1.40-1.5 0 (m, 2H), 1.50-1.60 (m,6H), 1.60-1.75 (m, 4H), 2.60=2.70 (mn, 2H), 3.00 (m, 1H), 3.60-3.75 (m,3H), 3.95-4 .00 (m, 2H), 4.52 (s, 2H), 4.75 (m, 1H), 4.88 (m, 1H), 6.89(d, J=14 Hz, 1H), 7.00-7.05 (m, 2H), 7.20-7.40 (m, 9H), 8.10 (m, 1H),8.20-8.30 (m, 3H), 8.60 (m, 1H), 11.02 (br s, 1H); t_(R)=7.47 min; MS(high res) calc'd for C₃₅H₄₉N₆O₅: 633.3764. Found: 633.3762. Anal.Calc'd for C₃₅H₄₉N₆O₅.HCl: C, 59.57; H, 7.14; N, 11.91. Found: C, 59.74;H, 7.30; N, 11.72.

Reaction of 4-phenoxyphenylacetic acid (25.0 g, 110 mmol) andp-toluenesulfonic acid (5.0 g, 26 mmol) in absolute ethanol (150 mL) asin described in Preparation 1 gave 27.6 g (98%) of the desired productas a yellow oil: ¹H-NMR (d, DMSO) 1.18 (t, J=7.2 Hz, 3H), 3.64 (s, 2H),4.08 (q, J=7.2 Hz, 2H), 6.90-7.00 (m, 4H), 7.13 (t, J=7.5 Hz, 1H), 7.23(d, J=8.7 Hz, 2H), 7.40 (t, J=5.7 Hz, 2H); MS (ion spray) 257.2 (M+1);Anal. Calc'd for C₁₅H₁₆O₃: C, 74.98; H, 6.29. Found: C, 74.88; H, 6.31.

Reaction of the product of Preparation 90 (10.0 g, 39.0 mmol),N-bromosuccinimide (7.2 g, 40.2 mmol) and 48% HBr (4 drops) in carbontetrachloride (40 mL) as described in Preparation 2 gave 11.9 g (92%) ofthe desired product as a colorless oil: ¹H-NMR (d, DMSO) 1.21 (t, J=7.3Hz, 3H), 4.15-4.30 (m, 2H), 5.94 (s, 1H), 6.95-7.15 (m, 4H), 7.20 (m,1H), 7.40-7.50 (m, 2H), 7.52-7.70 (m, 2H); MS (FD) 334, 336 (M+); Anal.Calc'd for C₁₆H₁₅BrO₃.0.05CHCl3: C, 56.51; H, 4.45. Found: C, 56.85; H,4.27.

Reaction of the product of Preparation 91 (10.9 g, 33.0 mmol),4-nitroimidazole (4.5 g, 39.6 mmol) and potassium carbonate (13.4 g,99.0 mmol) in dimethylformamide (150 mL) as described in Preparation 3gave 5.92 g (49%) of the desired product as a yellow oil: ¹H-NMR (d,DMSO) 1.17 (t, J=6.8 Hz, 3H), 4.25 (q, J=7.2 Hz, 2H), 6.60 (s, 1H),7.00-7.10 (m, 4H), 7.17 (t, J=7.2 Hz, 1H), 7.43 (t, J=6.0 Hz, 2H), 7.53(d, J=6.8 Hz, 2H), 7.94 (s, 1H), 8.41 (s, 1H); MS (ion spray) 368.2(M+1); Anal. Calc'd for C₁₉H₁₇N₃O₅.0.15CHCl3: C, 59.30; H, 4.49; N,10.91. Found: C, 59.55; H, 4.73; N, 10.97.

Reaction of the product of Preparation 92 (1.58 (4.3 mmol) with 10%palladium on carbon (0.8 g) in tetrahydrofuran (70 mL) followed bycoupling with the product of Preparation 1d (1.64 g, 4.3 mmol),1-hydroxybenzotriazole (0.7 g, 4.7 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.04 g, 4.7 mmol) asdescribed in Preparation 4 gave 1.92 g (62%) of the desired product as atan foam: ¹H-NMR (d, DMSO) 1.20 (t, J=7.2 Hz, 3H), 1.25-1.35 (m, 15H),3.57 (m, 1H), 3.70 (m, 1H)., 4.25 (q, J=7.2 Hz, 2H), 4.45-4.47 (m, 2H),4.60 (m, 1H), 6.43 (s, 1H), 7.00-7.10 (m, 4H), 7.20 (m, 1H), 7.25-7.35(m, 6H), 7.35-7.45 (m, 6H), 7.55 (s, 1H), 10.20 (br s, 1H); MS (ionspray) 700.7 (M+1); Anal. Calc'd for C₃₈H₄₅N₅O₈: C, 65.22; H, 6.48; N,10.01. Found: C, 65.12; H, 6.43; N, 9.87.

Reaction of the product of Preparation 93 (1.72 g, 2.5 mmol) and lithiumhydroxide (0.07 g, 3.0 mmol) in dioxane (50 mL) and water (25 mL) asdescribed in Preparation 5 gave 1.68 g (100%) of the desired product asa tan foam: ¹H-NMR (d, DMSO) 1.25-1.40 (m, 15H), 3.60 (m, 1H), 3.70 (m,1H), 4.45-4.50 (m, 2H), 4.57 (m, 1H), 6.25 (s, 1H), 7.00-7.07 (m, 4H),7.15-7.35 (m, 8H), 7.35-7.45 (m, 5H), 7.55 (s, 1H), 10.20 (br s, 1H),13.55 (br s, 1H); MS (ion spray) 672.6 (M+1); Anal. Calc'd forC₃₆H₄₁N₅O₈: C, 64.37; H, 6.15; N, 10.43. Found: C, 64.56; H, 6.37; N,10.23.

Reaction of the product of Preparation 94 (0.45 g, 0.67 mmol),pyrrolidine (0.07 mL, 0.67 mmol), 1-hydroxybenzotriazole (0.1 g, 0.74mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.15 g, 0.74mmol)in dimethylformamide (30 mL) as described in Preparation 6 gave0.22 g (45%) of the desired product as a white foam: ¹H-NMR (d, DMSO)1.20-1.40 (m, 15H), 1.65-1.90 (m, 4H), 3.05 (m, 1H), 3.25-3.45 (m, 2H),3.55-3.75 (m, 3H), 4.45-4.50 (m, 2H), 4.60(m, 1H), 6.43 (s, 1H), 7.05(t, J=8.7 Hz, 3H), 7.20 (m, 1H), 7.25-7.30 (m, 7H), 7.35-7.50 (m, 7H),10.20 (br s, 1H); MS (ion spray) 725.7 (M+1) ; Anal. Calc'd forC₄₀H₄₈N₆O₇: C, 66.28; H, 6.68; N, 11.59. Found: C, 66.42; H, 6.68; N,11.59.

Example 44

Reaction of the product of Preparation 95 (0.22 g, 0.3 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.2 g (100%) of the desired mixture of isomers: ¹H-NMR(d, DMSO) 1.45-1.55 (m, 6H), 1.70-1.90 (m, 4H), 2.95 (m, 1H), 3.25-3.45(m, 2H), 3.50-3.90 (m, 3H), 4.45-4.55 (m, 2H), 4.75 (m, 1H), 6.60 (m,1H), 7.00-(m, 3H), 7.20 (m, 1H), 7.25-7.50 (m, 12H), 7.98 (m, 1H),8.15-8.30 (m, 3H), 8.52 (t, J=7.6 Hz, 1H), 10.88 (br s, 1H); MS (ionspray) 625.4 (M+1); Anal. Calc'd for C₃₅H₄₀N₆O₅.2HCl; C, 60.26; H, 6.07;N, 12.05. Found: C, 60.02; H, 6.01; N, 11.81.

Reaction of the product of Preparation 94 (0.6 g, 0.9 mmol),4-methylpiperidine (0.1 ML, 0.9 mmol), 1-hydroxybenzotriazole (0.14 g,1.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.2 g, 1.0mmol) in dimethylformamide (30 mL) as described in Preparation 6 gave0.4 g (59%) of the desired product as a white foam: ¹H-NMR is consistentwith structure; MS (ion spray) 753.5 (M+1); Anal Calc'd for C₄₂H₅₂N₆O₇:C, 67.00; H, 6.96; N, 11.16. Found: C, 66.73; H, 6.91; N, 11.04.

Example 45

Reaction of the product of Preparation 96 (0.34 g, 0.45 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.27 g (83%) of the desired mixture of isomers as a whitesolid: ¹H-NMR is consistent with structure; MS (high res) calc'd forC₃₇H₄₅N₆O₅: 653.3451. Found: 653.3446.

Reaction of biphenylacetic acid (25.2 g, 119 mmol) and p-toluenesulfonicacid (3.3 g, 17 mmol) in absolute ethanol (250 mL) as described inPreparation 1 gave 25.4 g (89%) of the desired product as a yellow oil:¹H-NMR is consistent with structure; MS (FD) 240.1 (M+); Anal. Calc'dfor C₁₆H₁₆O₂: C, 79.97; H, 6.71. Found: C, 79.75; H, 6.59.

Reaction of the product of Preparation 97 (18.0 g, 75.0 mmol),N-bromosuccinimide (13.7 g, 77.25 mL) and 48% HBr (4 drops) in carbontetrachloride (80 mL) as described in Preparation 2 gave 22.56 g (94%)of the desired product as a yellow oil: ¹H-NMR is consistent withstructure; MS (FD) 318, 320 (M+); Anal. Calc'd forC₁₆H₁₅BrO₂.0.05Chydrochloric acid₃: C, 60.21; H, 4.74. Found: C, 59.50;H, 4.75.

To a slurry of sodium hydride (2.42 g, 60.5 mmol) stirring indimethylformamide (200 mL) at room temperature was added4-nitroimidazole (6.9 g, 60.5 mmol). After 10 min, the product ofPreparation 98 (17.62 g, 55.0 mmol) was added. After 16 h, the reactionmixture was concentrated and the residue was slurried in ethyl acetatethen filtered. The resulting oil was partitioned between ethyl acetateand water then extracted with ethyl acetate. The combined organicextracts were washed with brine, dried over sodium sulfate, filtered andconcentrated. The resulting oil was absorbed onto silica gel andpurified by flash chromatography (silica gel, 30-50% ethylacetate/hexanes) to yield 12.0 g (62%) of the desired product as ayellow viscous oil: ¹H-NMR is consistent with structure; MS (FD) 351(M+).

Reduction of the product of Preparation 99 (2.0 g, 5.8 mmol) under ahydrogen atmosphere with 10% palladium on carbon (0.8 g) andtetrahydrofuran (70 mL) followed by coupling with the product ofPreparation id (2.2 g, 5.8 mmol), 1-hydroxybenzotriazole (0.86 g, 6.4mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.3 g, 6.4mmol) as described in Preparation 4 gave 0.7 g (18%) of the desiredproduct as a tan foam: ¹H-NMR is consistent with structure; MS (FD) 683(M+); Anal. Calc'd for C₃₈H₄₅N₅O₇: C, 66.75; H, 6.63; N, 10.34. Found:C, 66.79; H, 6.48; N, 10.32.

Reaction of the product of Preparation 100 (0.7 g, 1.0 mmol) and lithiumhydroxide (0.03 g, 1.2 mmol) in dioxane (20 mL) and water (10 mL) asdescribed in Preparation 5 gave 0.66 g (100%) of the desired product asa tan foam: ¹H-NMR is consistent with structure; MS (FD) 656 (M+); Anal.Calc'd for C₃₆H₄₁N₅O₇: C, 65.94; H, 6.30; N, 10.68. Found: C, 65.90; H,6.37; N, 10.42.

Reaction of the product of Preparation 101 (0.7 g, 1.1 mmol) withy4-methylpiperidine (0.13 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.17 g,1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.25 g, 1.2mmol) in dimethylformamide (40 mL)as described in Preparation 6 gave0.52 g (65%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 728.4 (M+); Anal. Calc'd for C₃₇H₄₇F₃N₆O₆: C,60.98; H, 6.50; N, 11.53. Found: C, 61.18; H, 6.35; N, 11.44.

Examples 46 and 47

Reaction of the product of Preparation 102 (0.36 g, 0.49 mmol) andtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as described inExample 1 gave 0.3 g (88%) of the desired mixture of isomers. Resolutionof the diastereomers (4 g, 3.6 mmol) by HPLC (Kromsil CHI-DMP chiralstationary phase, 3A alcohol/dimethylethylamine/heptane eluant) providedprovided 0.6 (16%) of isomer 1 and 0.5 mg (12%) of isomer 2, bothisolated as white solids after formation of their respectivehydrochloride salts as described in Example 7:

Example 46 (isomer 1) ¹H-NMR is consistent with structure; t_(R)=6.9min; MS (ion spray) 637.4 (M+1); Anal. Calc'd for C₃₇H₄₄N₆O₄.2.5HCl: C,61.05; H, 6.44; N, 11.54. Found: C, 60.89; H, 6.53; N, 11.25.

Example 47 (isomer 2) ¹H-NMR is consistent with structure; t_(R)=9.2min; MS (ion spray) 637.4 (M+1); Anal. Calc'd for C₃₇H₄₄N₆O₄.2.6HCl: C,60.75; H, 6.42; N, 11.49. Found: C, 60.67; H, 6.63; N, 11.18.

Reaction of 3-fluorophenylacetic acid (15.0 g, 97.0 mmol) andp-toluenesulfonic acid (3.0 g, 16 mmol) in absolute ethanol as describedin Preparation 1 gave 16.5 g (94%) of the desired product as a colorlessoil: ¹H-NMR is consistent with structure; MS (FD) 182 (M+) ; Anal.Calc'd for C₁₀H₁₁FO₂: C, 65.92; H, 6.09. Found: C, 64.94; H, 5.99.

Reaction of the product of Preparation 103 (15.0 g, 82 mmol),N-bromosuccinimide (15.0 g, 84.5 mmol) and 48% HBr (4 drops) in carbontetrachloride (80 mL) as described in Preparation 2 gave 19.2 g (90%) ofthe desired product as a colorless oil: ¹H-NMR is consistent withstructure; MS (FD) 259, 261 (M+); Anal. Calc'd for C₁₀H₁₀BrFO₂: C,46.00; H, 3.86. Found: C, 45.71; H, 3.90.

Reaction of the product of Preparation 104 (15.0 g, 58.0 mmol),4-nitroimidazole (7.8 g, 63.8 mmol) and sodium hydride ((2.8 g, 63.8mmol) in dimethylformamide (200 mL) as in described in Preparation 3gave 11.13 g (65%) of the desired product as a yellow oil: ¹H-NMR isconsistent with structure; MS (FD) 293 (M+); Anal. Calc'd forC₁₃H₁₂FN₃O₄: C, 53.24; H, 4.12; N, 14.33. Found: C, 53.12; H, 4.22; N,14.47.

Reaction of the product of Preparation 105 (1.7 g, 5.8 mmol) with 10%palladium on carbon (0.7 g) in tetrahydrofuran (40 mL) under a hydrogenatmosphere followed by coupling with the product of Preparation 1d (2.2g, 5.8 mmol), 1-hydroxybenzotriazole (0.86 g, 6.4 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.3 g, 6.4 mmol) asdescribed in Preparation 4 gave 2.05 g (60%) of the desired product as ayellow foam: ¹H-NMR is consistent with structure; MS (FD) 625 (M+);Anal. Calc'd for C₃₂H₄₀FN₅O₇: C, 61.43; H, 6.44; N, 11.19. Found: C,61.28; H, 6.64; N, 11.32.

Reaction of the product of Preparation 104 (0.12 g, 3.2 mmol) andlithium hydroxide (0.09 g, 3.84 mmol) in dioxane (40 mL) and water (20mL) as described in Preparation 5 gave 1.91 g (100%) of the desiredproduct as a tan foam: ¹H-NMR is consistent with structure; MS (FD) 598(M+); Anal. Calc'd for C₃₀H₃₆FN₅O₇: C, 60.29; H, 6.07; N, 11.72. Found:C, 60.21; H, 6.41; N, 11.06.

Reaction of the product of Preparation 106 (0.7 g, 1.2 mmol),4-methylpiperidine (0.14 mL, 1.2 mmol), 1-hydroxybenzotriazole (0.18 g,1.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.3mmol) in dimethylformamide (100 mL) as described in Preparation 6 gave0.52 g (64%) of the desired product as a white solid: ¹H-NMR isconsistent with structure; MS (FD) 678 (M+); Anal. Calc'd forC₃₆H₄₇FN₆O₆: C, 63.70; H, 6.98; N, 12.38. Found: C, 63.62; H, 7.10; N,12.31.

Example 48

Reaction of the product of Preparation 107 (0.51 g, 0.75 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.24 g (49%) of the desired mixture of isomers as ayellow solid: ¹H-NMR is consistent with structure; MS (FD) 578 (M+);Anal. Calc'd for C₃₁H₃₉FN₆O₄.2.7HCl: C, 54.99; H, 6.21; N, 12.41. Found:C, 54.97; H, 6.23; N, 12.40.

Reaction of the product of Preparation 106 (0.7 g, 1.2 mmol),pyrrolidine (0.1 mL, 1.2 mmol), 1-hydroxybenzotriazole (0.18 g, 1.3mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.3mmol) in dimethylformamide (40 mL) as described in Preparation 6 gave0.54 g (69%) of the desired product as a yellow foam: ¹H-NMR isconsistent with structure; MS (FD) 650 (M+); Anal. Calc'd forC₃₄H₄₃FN₆O₆.0.2CHCl3: C, 60.89; H, 6.45; N, 12.46. Found: C, 60.91; H,6.39; N, 12.36.

Example 49

Reaction of the product of Preparation 108 (0.4 g, 0.6 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.3 g (79%) of the desired mixture of isomers as a yellowsolid: ¹H-NMR is consistent with structure; MS (FD) 550 (M+); Anal.Calc'd for C₂₉H₃₅FN₆O₄.2.2HCl: C, 55.21; H, 5.94; N, 13.32. Found: C,55.07; H, 5.91; N, 12.53.

Reaction of 2-fluorophenylacetic acid (15.0 g, 97.0 mmol) andp-toluenesulfonic acid (2.8 g, 14.5 mmol) in absolute ethanol (100 mL)as described in Preparation 1 gave 17.0 g (96%) of the desired productas a colorless oil: ¹H-NMR is consistent with structure; MS (FD) 182(M+).

Reaction of the product of Preparation 109 (15.0 g, 82 mmol),N-bromosuccinimde (15.0 g, 84.5 mmol) and 48% HBr (3 drops) in carbontetrachloride (80 mL) as described in Preparation 2 gave 21 g (98%) ofthe desired product as a colorless oil: ¹H-NMR is consistent withstructure; MS (FD) 260 (M+).

Reaction of the product of Preparation 110 (15.0 g, 58 mmol),4-nitroimidazole (7.8 g, 63.8 mmol) and sodium hydride (2.8 g, 63.8mmol) in dimethylformamide (200 mL) as described in Preparation 3 gave11.36 g (67%) of the desired product as a white solid: ¹H-NMR isconsistent with structure; MS (FD) 293.1 (M+); Anal. Calc'd forC₁₃H₁₂FN₃O₄: C, 53.24; H, 4.12; N, 14.33. Found: C, 53.54; H, 4.18; N,14.11.

Reaction of the product of Preparation 111 (1.7 g, 5.8 mmol) with 10%palladium on carbon (0.7 g) in tetrahydrofuran (50 mL) under a hydrogenatmosphere followed by coupling with the product of Preparation 1d (2.2g, 5.8 mmol), 1-hydroxybenzotriazole (0.86 g, 6.4 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.3 g, 6.4 mmol) asdescribed in Preparation 4 gave 2.4 g (67%) of the desired product as atan foam: ¹H-NMR is consistent with structure; MS (FD) 625 (M+); Anal.Calc'd for C₃₂H₄₀FN₅O₇: C, 61.43; H, 6.44; N, 11.19. Found: C, 61.51; H,6.50; N, 11.34.

Reaction of the product of Preparation 112 (2.35 g, 3.8 mmol) andlithium hydroxide (0.1 g, 4.6 mmol) in dioxane (40 mL) and water (20 mL)as desribed in Preparation 5 gave 2.27 g (100%) of the desired productas a tan foam: ¹H-NMR is consistent with structure; MS (FD) 598 (M+);Anal. Calc'd for C₃₀H₃₆FN₅O₇: C, 60.29; H, 6.07; H, 11.72. Found: C,60.08; H, 6.28; N, 11.42.

Reaction of the product of Preparation 113 (0.7 g, 1,2 mmol),4-methylpiperidine (0.14 mL, 1.2 mmol), 1-hydroxybenzotriazole (0.18 g,1.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.3mmol) in dimethylformamide (100 mL) as described in Preparation 6 gave0.56 g (69%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 678.2 (M+); Anal. Calc'd for C₃₆H₄₇FN₆O₆: C,63.70; H, 6.98; N, 12.38. Found: C, 63.44; H, 7.05; N, 12.10.

Example 50

Reaction of the product of Preparation 114 (0.53 g, 0.78 mmol) andtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as described inExample 1 gave 0.38 g (75%) of the desired mixture of isomers as ayellow solid: ¹H-NMR is consistent with structure; MS (FD) 578 (M+);Anal. Calc'd for C₃₁H₃₉FN₆O₄.2.2HCl: C, 56.51; H, 6.30; N, 12.75. Found:C, 56.45; H, 6.10; N, 12.43.

Reaction of the product of Preparation 113 (0.7 g, 1.2 mmol),pyrrolidine (0.1 mL, 1.2 mmol), 1-hydroxybenzotriazole (0.18 g, 1.3mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.3mmol) in dimethylformamide (100 mL) as described in Preparation 6 gave0.6 g (77%) of the desired product as a tan foam. ¹H-NMR is consistentwith structure; MS (FD) 650 (M+); Anal. Calc'd for C₃₄H₄₃FN₆O₆: C,62.75; H, 6.66; N, 12.91. Found: C, 62.53; H, 6.58; N, 12.71.

Example 51

Reaction of the product of Preparation 115 (0.46 g, 0.7 mmol) andtrifluoroacetic acid (4 mL) indichloromethane (12 mL) as described inExample 1 gave 0.44 g (100%) of the desired mixture of isomers as awhite foam: ¹H-NMR is consistent with structure. MS (high res) calc'dfor C₂₉H₃₆FN₆O₄: 551.2782. Found: C, 551.2779. Anal. Calc'd forC₂₉H₃₅FN₆O₄.2HCl: C, 55.86; H, 5.98; N, 13.48. Found: C, 56.09; H, 5.91;N, 13.44.

Reaction of 3-trifluoromethylphenylacetic acid (15.0 g, 73.4 mmol) andp-toluenesulfonic acid (3 g, 15.6 mmol) in absolute ethanol (200 mL) asdescribed in Preparation 1 gave 15.6 g (93%) of the desired product as acolorless oil: ¹H-NMR is consistent with structure; MS (FD) 232 (M+);Anal. Calc'd for C₁₁H₁₁F₃O₂: C, 56.90; H, 4.77. Found: C, 56.93; H,4.65.

Reaction of the product of Preparation 116 (10.0 g, 44.0 mmol),N-bromosuccinimide (8.0 g, 45.3 mmol) and 48% HBr (4 drops) in carbontetrachloride (70 mL), as desribed in Preparation 2 gave 11.2 g (82%) ofthe desired product as a colorless oil: ¹H-NMR is consistent withstructure; MS (FD) 264 (M+); Anal. Calc'd for C₁₁H₁₀BrF₃O₂: C, 42.47; H,3.24. Found: C, 42.37; H, 3.26.

Reaction of the product of Preparation 117 (11.2 g, 36.0 mmol),4-nitroimidazole (4.9 g, 43.2 mmol) and sodium hydride (1.7 g, 43.2mmol) in dimethylformamide (180 mL) as described in Preparation 3 gave6.22 g (50%) of the desired product as a yellow oil: ¹H-NMR isconsistent with structure; MS (FD) 343.1 (M+); Anal. Calc'd forC₁₄H₁₂F₃N₃O₄: C, 48.99; H, 3.52; N, 12.24. Found: C, 48.74; H, 3.63; N,12.06.

Reaction of the product of Preparation 118 (2.0 g, 5.8 mmol) with 10%palladium on carbon (0.6 g) in tetrahydrofuran (80 mL) under anatmosphere of hydrogen followed by coupling with the product ofPreparation 1d (2.2 g, 5.8 mmol), 1-hydroxybenzotriazole (0.86 g, 6.4mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.3 g, 6.4mmol) as described in Preparation 4 gave 1.82 g (47%) of the desiredproduct as a tan foam: ¹H-NMR is consistent with structure; MS (FD)675.4 (M+); Anal. Calc'd for C₃₃H₄₀F₃N₅O₇: C, 58.66; H( 5.97; N, 10.36.Found: C, 58.67; H, 5.87; N, 10.51.

Reaction of the product of Preparation 120 (1.67 g, 2.5 mmol) andlithium hydroxide (0.07 g, 2.8 mmol) in dioxane (40 mL) and water (20mL) as described in Preparation 5 gave 1.60 g (99%) of the desiredproduct as a yellow foam: ¹H-NMR is consistent with structure; MS (FD)648 (M+); Anal. Calc'd for C₃₁H₃₆F₃N₅O₇: C, 57.49; H, 5.60; N, 10.81.Found: C, 57.52; H, 5.62; N, 10.75.

Reaction of the product of Preparation 120 (0.6 g, 0.93 mmol),4-methylpiperidine (0.11 mL, 0.93 mmol), 1-hydroxybenzotriazole (0.13 g,1.02 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.12 g,1.02 mmol)in dimethylformamide (40 mL) as described in Preparation 6gave 0.55 g (81%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 728.9 (M+); Anal. Calc'd forC₃₇H₄₇F₃N₆O₆: C, 60.98; H, 6.50; N, 11.53. Found: C, 60.81; H, 6.57; N,11.69.

Example 52

Reaction of the product of Preparation 121 (0.5 g, 0.68 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.33 g (69%) of the desired mixture of isomers as ayellow solid: ¹H-NMR is consistent with structure; MS (ion spray) 628.8(M+1); Anal. Calc'd for C₃₂H₃₉F₃N₆O₄.2.3HCl: C, 53.94; H, 5.84; N,11.79. Found: C, 53.89; H, 5.92; N, 11.65.

Reaction of 3-trifluoromethylphenylacetic acid (15.0 g, 73.4 mmol) andp-toluenesulfonic acid (2.8 g, 14.5 mmol)in absolute ethanol (200 mL) asdescribed in Preparation 1 gave 16.11 g (94%) of the desired product asa colorless oil: 1H-NMR is consistent with structure; MS (FD) 232 (M+).Anal. Calc'd for C₁₁H₁₁F₃O₂: C, 56.90; H, 4.77. Found: C, 56.64; H,4.90.

Reaction of the product of Preparation 122 (15.0 g, 65 mmol),N-bromosuccinimide (11.9 g, 67.0 mmol) and 48% HBr (4 drops) in carbontetrachloride (80 mL) as described in Preparation 2 gave 17.1 g (85%) ofthe desired product as a colorless oil: ¹H-NMR is consistent withstructure; MS (FD) 311, 313 (M+).

Reaction of the product of Preparation 123 (15.0 g, 48.0 mmol),4-nitroimidazole (6.0 g, 52.8 mmol) and sodium hydride (2.1 g, 52.8mmol) in dimethylformamide (200 mL) as described in Preparation 3 gave12.25 g (74%) of the desired product as a yellow oil: ¹H-NMR isconsistent with structure; MS (FD) 343 (M+); Anal. Calc'd forC₁₄H₁₂F₃N₃O₄: C, 48.99; H, 3.52; N, 12.24. Found: C, 49.10; H, 3.58; H,12.22.

Reaction of the product of Preparation 124 (2.0 g, 5.8 mmol) with 10%palladium on carbon (1.0 g)in tetrahydrofuran (60 mL) under a hydrogenatmosphere followed by coupling with the product of Preparation 1d (2.2g, 5.8 mmol), 1-hydroxybenzotriazole (0.86 g, 6.4 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.3 g, 6.4 mmol) asdescribed in Preparation 4 gave 3.16 g (93%) of the desired product as atan foam: ¹H-NMR is consistent with structure; MS (FD) 675.4 (M+); Anal.Calc'd for C₃₃H₄₀F₃N₅O₇: C, 58.66; H, 5.97; N, 10.36. Found: C, 58.81;H, 6.04; N, 10.12.

Reaction of the product of Preparation 125 (2.78 g, 4.1 mmol) withlithium hydroxide (0.12 g, 4.9 mmol) in dioxane (40 mL) and water (20mL) as described in Preparation 5 gave 2.6 g (98%) of the desiredproduct as a yellow foam: ¹H-NMR is consistent with structure; MS (FD)648.2 (M+); Anal. Calc'd for C₃₁H₃₆F₃N₆O₇: C, 57.49; H, 5.60; N, 10.81.Found: C, 58.06; H, 6.14; N, 10.27.

Reaction of the product of Preparation 126 (0.7 g, 1.1 mmol),4-methylpiperidine (0.13 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.17 g,1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.25 g, 1.2mmol)in dimethylformamide (30 mL) as described in Preparation 6 gave0.32 g (40%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 728 (M+); Anal. Calc'd for C₃₇H₄₇F₃N₆O₆: C,60.98; H, 6.50; N, 11.53. Found: C, 60.76; H, 6.59; N, 11.36.

Example 53

Reaction of the product of Preparation 127 (0.3 g, 0.41 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.28 g (97%) of the desired mixture of isomers as a whitesolid: ¹H-NMR is consistent with structure; MS (FD) 628 (M+); Anal.Calc'd for C₃₂H₃₉F₃N₆O₄.2.2HCl: C, 54.22; H, 5.86; N, 11.85. Found: C,54.33; H, 5.84; N, 11.56.

Reaction of the product of Preparation 126 (0.5 g, 0.77 mmol),pyrrolidine (0.07 mL, 0.77 mmol), 1-hydroxybenzotriazole (0.12 g, 0.85mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.18 g, 0.85mmol) in dimethylformamide (30 mL) as described in Preparation 6 gave0.2 g (37%) of the desired product as a tan solid: ¹H-NMR is consistentwith structure; MS (FD) 700 (M+); Anal. Calc'd for C₃₅H₄₃F₃N₆O₆.0.4H₂O:C, 59.38; H, 6.24; N, 11.87. Found: C, 59.17; H, 6.24; N, 11.87.

Example 54

Reaction of the product of Preparation 128 (0.2 g, 0.29 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.18 g (100%) of the desired mixture of isomers as awhite solid: ¹H-NMR is consistent with structure; MS (FD) 600 (M+).

Reaction of the product of preparation 126 (0.75 g, 1.2 mmol),dimethylamine hydrochloride (0.1 g, 1.2 mmol), triethylamine (0.19 g,1.3 mmol), 1-hydroxybenzotriazole (0.18 g, 1.3 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.3 mmol) indimethylformamide (40 mL) as described in Preparation 6 gave 0.49 g(60%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 675 (M+); Anal. Calc'd for C:₃₃H₄₁F₃N₆O₆: C, 58.75;H, 6.13; N, 12.46. Found: C, 58.69; H, 6.12; N, 12.28.

Example 55

Reaction of the product of Preparation 129 (0.42 g, 0.62 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.3 g (75%) of the desired mixture of isomers as a yellowsolid: ¹H-NMR is consistent with structure; MS (FD) 574 (M+); Anal.Calc'd for C₂₈H₃₃F₃N₆O₄.2.8 HCl: C, 48.70; H, 5.33; N, 12.42. Found: C,49.84; H, 5.27: N, 12.09.

Reaction of the product of Preparation 126 (0.5 g, 0.77 mmol),4-(4-fluorobenzoyl)piperidine hydrochloride (0.19 g, 0.77 mmol),triethylamine (0.12 mL, 0.85 mmol), 1-hydroxybenzotriazole (0.12 g, 0.85mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.18 g, 0.85mmol) in dimethylformamide (40 mL) as described in Preparation 6 gave0.45 g (69%) of the desired product as a yellow foam: ¹H-NMR isconsistent with structure; MS (FD) 836.8 (M+); Anal. Calc'd forC₄₃H₄₈F₄N₆O₇.0.4H₂O: C, 61.19; H, 5.83; N, 9.96. Found: C, 60.92; H,5.56; N, 10.09.

Example 46

Reaction of the prodcut of Preparation 130 (0.4 g, 0.48 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.26 g (67%) of the desired mixture of isomers as a whitesolid. ¹H-NMR is consistent with structure; MS (FD) 736.7 (M+); Anal.Calc'd for C₃₈H₄₀F₄N₆O₅.2.1 HCl: C, 56.12; H, 5.22; N, 10.33. Found: C,56.08; H, 5.46; N, 10.38.

Reaction of alpha-bromocyclohexylacetic acid (5.0 g, 21.0 mmol),4-nitroimidiazole (2.6 g, 23.1 mmol) and sodium hydride (0.93 g, 23.1mmol) in dimethylformamide (45 mL) as described in Preparation 3 gave1.9 g (34%) of the desired product as a clear oil: ¹H-NMR is consistentwith structure; MS (ion spray) 268 (M+1); Anal. Calc'd for C₁₂H₁₇N₃O₄:C, 53.92; H, 6.41; N, 15.72. Found: C, 53.63; H, 6.33; N, 15.77.

Reaction of the product of Preparation 131 (1.4 g, 5.2 mmol) with 10%palladium on carbon (0.8 g) in tetrahydrofuran (60 mL) under a hydrogenatmosphere followed by coupling with the product of Preparation 1d (2.0g, 5.2 mmol), 1-hydroxybenzotriazole (0.8 g, 5.7 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.2 g, 5.7 mmol) asdescribed in Preparation 4 gave 2.09 g (65%) of the desired product as atan foam. ¹H-NMR is consistent with structure; MS (ion spray) 600.4(M+1); Anal. Calc'd for C₃₁H₄₅N₅O₇: C, 62.08; H, 7.56; N, 11.68. Found:C, 62.04; H, 7.53; N, 11.74.

Reaction of the product of Preparation 132 (2.0 g, 3.3 mmol) withlithium hydroxide (0.1 g, 4.0 mmol) in dioxane (50 mL) and water (25 mL)as described in Preparation 5 gave 1.9 g (99%) of the desired product asa tan foam: ¹H-NMR is consistent with structure; MS (ion spray) 586.4(M+1); Anal. Calc'd for C₃₀H₄₃N₅O₇: C, 61.52; H, 7.40; N. 11.96. Found:C, 61.41; H, 7.42; N, 11.82.

Reaction of the product of Preparation 133 (0.8 g, 1.4 mmol),4-methylpiperidine (0.17 mL, 1.4 mmol), 1-hydroxybenzotriazole (0.21 g,1.54 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.32 g,1.54 mmol) in dimethylformamide (30 mL) as described in Preparation 6gave 0.92 g (99%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (ion spray) 667.5 (M+1); Anal. Calc'd forC₃₆H₅₄N₆O₆: C, 64.84; H, 8.16; N, 12.60. Found: C, 64.55; H, 7.73; N,12.26.

Example 57

Reaction of the product of Preparation 134 (0.7 g, 1.0 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.43 g (64%) of the desired mixture of isomers as a tansolid: ¹H-NMR is consistent with structure; MS (ion spray) 567.6 (M+l);Anal. Calc'd for C₃₁H₄₆N₆O₄.2HCl: C, 58.21; H, 7.56; N, 13.14. Found: C,58.36; H, 7.33; N, 13.19.

Reaction of the product of Preparation 133 (0.8 g, 1.4 mmol),dimethylamine hydrochloride (0.12 g, 1.4 mmol), triethylamine (0.22 ML,1.54 mmol), 1-hydroxybenzotriazole (0.21 g, 1.54 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.32 g, 1.54 mmol) indimethylformamide (30 mL) as described in Preparation 6 gave 0.86 g(100%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (ion spray) 613.4 (M+1); Anal. Calc'd for C₃₂H₄₈N₆O₆: C,62.72; H, 7.90; N, 13.72. Found: C, 62.44; H, 7.64; N, 13.57.

Example 58

Reaction of the product of Preparation 135 (0.7 g, 1.0 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 1 gave 0.43 g (64%) of the desired mixture of isomers as a tansolid: ¹H-NMR is consistent with structure; MS (ion spray) 567.6 (M+1)Anal. Calc'd for C₃₁H₄₆N₆O₄.2HCl: C, 58.21; H, 7.56; N, 13.14. Found: C,58.36; H, 7.33; N, 13.19.

To a suspension of 2-naphthyl acetic acid (49.37 g, 265.0 mmol) incarbon tetrachloride (55 mL) was added and thionyl chloride (80 mL). Themixture was heated to reflux for 20 minutes then cooled to ambienttemperature. Carbon tetrachloride (125 mL), N-bromosuccinimide (56.60 g,318.0 mmol) and hydrobromic acid (48% aq., 0.5 mL) were added. Themixture was heated to reflux for 30 min, cooled to ambient temperature,filtered, and concentrated. The resulting material was dissolved indichloromethane (200 mL) and excess ethanol (100 mL) was added dropwise.After 1 h, the reaction was concentrated and the resulting crudematerial was purified by flash chromatography(silica gel, 30% ethylacetate/hexane) to yield a tan solid. This crude material was dissolveddimethylformamide (200 mL) and 4-nitroimidazole (29.78 g, 263.5 mmol)and potassium carbonate (72.70 g, 526.8 mmol) were added. After 16 h,the reaction was concentrated to 100 mL. Ethyl acetate and water wereadded and the mixture washed with sodium bicarbonate and brine. Theorganic layer was dried over sodium sulfate and concentrated. The crudematerial was was purified by flash chromatography (silica, 30% ethylacetate/hexane) to yield 40.2 g (47%) of the desired product as a brownfoam: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal. calcd.for C₁₇H₁₅N₃O₄; 62.76; C, 4.65; H, 12.92; N. found 60.54; C, 4.35; H,12.04; N. ISMS (M+) - 326.

Reaction of the product of Preparation 136 (4.80 g, 14.77 mmol) with 5%palladium on carbon (2.5 g) in tetrahydrofuran (100 mL) under a hydrogenatmosphere followed by coupling with the product of Preparation 1d (5.61g, 14.77 mmol), EDCI (2.79 g, 16.25 mmol), 1-hydroxybenzotriazole (2.00g, 14.77 mmol) , and N-methylmorpholine (16 mL, 14.77 mmol) as describedin Preparation 4 gave (6.04 g, 62%) of the desired product as a lightorange foam: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal.calcd. for C₃₆H₄₃N₅O₇; 65.74; C, 6.59; H, 10.65; N. found 64.02; C,6.09; H, 10.13 N. ISMS (M+)—658.

A solution of lithium hydroxide (0.38 g, 9.16 mmol) in water (50 mL) wasadded to a solution of the product of Preparation 137 (6.04 g, 9.16mmol) in tetrahydrofuran (100 mL). After 30 min, water was added and themixture washed with diethyl ether. The aqueous layer was adjusted topH=3.0 with sodium bisulfate, saturated with sodium chloride, and washedwith ethyl acetate. The combined organic extracts were dried over sodiumsulfate, and concentrated. To the resulting crude material stirring atroom temperature in dimethylformamide (50 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.08 g, 10.01 mmol),1-hydroxybenzotriazole (1.24 g, 9.16 mmol) and 4-methylpiperidine (1.1mL, 9.16 mmol). After 18 h, the reaction was quenched with saturatedbicarbonate, and washed with ethyl acetate. The combined organicextracts were washed with brine, dried over sodium sulfate, andconcentrated. The crude material was purified by flash chromatography(silica gel, 5% methanol/dichloromethane) to yield 4.9 g (75%) of thedesired product as a pale yellow foam: ¹H NMR (300 MHz,CDCl₃)—consistent with structure; Anal. calcd. for C₄₀H₅₀N₆O₆; 67.58; C,7.09; H, 11.82; N. found 65.60; C, 7.09; H, 11.50; N. ISMS (M+)—711.

Examples 59 and 60

To a solution of of the product of Preparation 138 (4.90 g, 6.89 mmol)stirring at room temperature in dichloromethane (40 mL) and anisole (1.0mL) was added to triflouroacetic acid (10 mL). After 3 hours, thereaction was quenched with saturated sodium bicarbonate and extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried over sodium sulfate and concentrated. The resulting crudematerial was purified by flash chromatography (silica gel, 5%methanol/dichloromethane) to give the product as a mixture ofdiastereomers. This material was resolved by HPLC (Kromsil CHI-DMPchiral stationary phase, 3A alcohol/dimethylethylamine/heptane eluant)to provide the free amine of the desired products. The individualdiastereomers were dissolved in ethyl acetate and treated with asaturated solution of hydrochloric acid in diethyl ether. The resultingprecipiate was filtered to yield the desired products (426779—0.64 g,14%) (426780—0.43 g, 9%) as tan solids: Example 59. ¹H NMR (300 MHz,CDCl₃)—consistent with structure; Anal. calcd. for C₃₅H₄₄N₆O₄Cl₂; 61.49;C, 6.49; H, 12.29; N. found 60.28; C, 6.38; H, 11.74; N. ISMS (M+)—611.Example 60. ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal.calcd. for C₃₅H₄₄N₆O₄Cl₂; 61.49; C, 6.49; H, 12.29; N. found 47.81; C,5.29; H, 9.83; N. ISMS (M+)—611.

Reaction of the product of Preparation 136 (1.31g, 4.02 mmol) with 10%palladium on carbon (0.5 g) in tetrahydrofuran (50 mL) under a hydrogenatmosphere followed by coupling with the product of Preparation 1j (1.52g, 4.02 mmol), 1-hydroxybenzotriazole (0.68 g, 4.42 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(0.91 g, 4.42 mmol) asdescribed in Preparation 4 to give 1.06 g (38%) of the title compound asa tan solid: ¹H NMR (d⁶-DMSO, d): 1.22(m, 18H), 1.50(m, 4H), 2.55(m,2H), 4.26(q, J=9.0 Hz, 2H), 4.37(bs, 1H), 5.75(s, 1H), 6.60(s, 1H),7.02(bs, 1H), 7.16(m, 3H), 7.22(m, 3H), 7.43(m, 1H), 7.50(d, J=9.3 Hz,2H), 7.60(m, 2H), 7.97(m, 3H), 10.21(m, 1H). Ion spray MS (M⁺+1): 656.

Reaction of the product of Preparation 139 (1.06 g, 1.62 mmol) withlithium hydroxide 75 mg, 1.78 mmol)in dioxane (30 mL) and water (15 mL)as described in Preparation 5 gave 1.01 g (100%) of the title compoundas a golden yellow solid: ¹H NMR (d⁶-DMSO, d): 1.20(m, 15H), 1.50(m,4H), 2.55(m, 2H), 4.38(bs, 1H), 6.58(s, 1H), 7.02(bs, 1H), 7.17(m, 3H),7.25(m, 3H), 7.35(m, 1H), 7.50(m, 2H), 7.58(m, 2H), 7.98(m, 3H), 8.09(m,1H), 10.36(bs, 1H). Ion spray MS (M⁺1): 628.

To a solution of the product of Preparation 140 (500 mg, 0.80 mmol)dimethylamine.hydrochloric acid (72 mg, 0.88 mmol), triethylamine (0.12mL, 0.88 mmol), 1-hydroxybenzotriazole (134 mg, 0.88 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (18 mg, 0.88 mmol) indimethylformamide (20 mL) as described in Preparation 6 gave 342 mg(66%) of the title compound as a white solid: ¹H NMR (d⁶-DMSO, d):1.27(m, 15H), 1.57(m, 4H), 2.55(m, 2H), 2.90(s, 3H), 2.95(s, 3H),4.38(bs, 1H), 6.80(s, 1H), 7.02(bs, 1H), 7.15(m, 3H), 7.22(m, 3H),7.35(m, 1H), 7.47(m, 2H), 7.57(m, 2H), 7.88(s, 1H), 7.98(m, 3H),10.15(bs, 1H). Ion spray MS (M⁺+1): 655.

Anal. (C₃₇H₄₆N₆O₅): H,N,C: calcd 67.87. found 66.19.

Example 61

Reaction of the product of Preparation 141 (333 mg, 0.51 mmol) withtrifluoroacetic acid (5 mL) in dichloromethane (17 mL) as described inExample 1 gave 52 mg (65%) of a tan solid which was purified by HPLC(Kromosil CHI-DMP chiral stationary phase, 3Aalcohol/dimethylethylamine/heptane eluant) to give the free amine whichwas acidied with hydrochloric acid to provide the desired product: ¹HNMR (d⁶-DMSO, d): 1.21(m, 6H), 1.57(m, 4H), 2.54(m, 2H), 2.90(s, 3H),2.95(s, 3H), 4.41(bs, 1H), 6.82(s, 1H), 7.02(bs, 1H), 7.14(m, 3H),7.24(m, 3H), 7.48(m, 2H), 7.57(m, 2H), 7.87(s, 1H), 7.97(m, 3H),8.12(bs, 1H), 10.40(s, 1H). FAB+exact MS (M⁺+1): 555.3084 calcd,555.3079 found Anal. (C₃₂H₄₁N₆O₃Cl₃): C,H,N.

Reaction of the product of Preparation 136 (8.7 g, 27 mmol) with 10%palladium on carbon (4.0 g) under a hydrogen atmosphere followed bycoupling with the product of Preparation 1d (10.14 g, 26.7 mmol),1-hydroxybenzotriazole (4.49 g, 29.3 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (6.05 g, 29.3 mmol) asdescribed in Preparation 4 gave 5.4 g (31%) of the title compound as atan solid: ¹H NMR (d⁶-DMSO, d): 1.26(t, J=7.4 Hz, 3H), 1.40(s, 9H),1.55(m, 6H), 3.55(m, 1H), 4.02(s, 1H), 4.25(m, 2H), 4.50(dd, J=10.0 Hz,2H), 4.86(s, 1H), 5.92(s, 1H), 7.02(d, J=7.0 Hz, 1H), 7.22(m, 8H),7.33(m, 3H), 7.41(s, 1H), 7.49(m, 1H), 7.80(m, 2H), 9.22(bs, 1H). Ionspray MS (M⁺+1): 658. Anal. (C₃₆H₄₃N₅O₇) :C,H,N.

Reaction of the product of Preparation 142 (5.39 g, 8.19 mmol) withlithium hydroxide (361 mg, 8.60 mmol) in dioxane (120 mL) and water (75mL) as described in Preparation 5 gave 4.92 g (95%) of the titlecompound as a golden yellow solid: ¹H NMR (d⁶-DMSO, d): 1.28 (m, 15H),3.57(m, 1H), 3.66(m, 1H), 4.43(s, 2H), 4.48(d, J=5.3 Hz, 1H), 4.56(bs,1H), 5.75(bs, 1H), 7.13(bs, 1H), 7.26(m, 6H), 7.31(d, J=6.0 Hz, 2H),7.40(m, 1H), 7.45(m, 2H), 7.65(s, 1H), 7.83(m, 3H), 10.10(bs, 1H). Ionspray MS (M⁺+1): 630.

Reaction of the product of Preparation 143 (4.88 g, 7.75 mmol),dimethylamine (4.2 mL, 8.53 mmol, 2.0M in tetrahydrofuran),1-hydroxy-7-azabenzotriazole(1.16 g, 8.53 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.76 g, 8.53 mmol) intetrahydrofuran (120 mL) as described in Preparation 6 gave 2.06 g(40%)of the title compound as a yellow foam: 4¹H NMR (d⁶-DMSO, d):1.28(m, 15H), 2.92(s, 3H), 2.95(s, 3H), 3.60(m, 1H), 4.43(d, J=4.5 Hz),4.57(bs, 1H), 6.83(s, 1H), 7.24(m, 8H), 7.39(m, 1H), 7.50(m, 1H),7.56(m, 2H), 7.88(s, 1H), 7.96(m, 3H). Ion spray MS (M⁺+1): 657 Anal.(C₃₆H₄₄N₆O₄): H,N;C: calcd 65.84; found 63.70.

Example 62

To a solution of glacial acetic acid saturated with dry hydrochloricacid (50 mL, ˜3N in hydrochloric acid) stirring at room temperature wasadded the product of Preparation 144 (1.87 g, 2.85 mmol). After 2h, thesolution was concentrated, washed with aqueous sodium bicarbonatesolution, dried over magnesium sulfate and concentratd. The resultingcrude material was purified by HPLC (Column) to give 0.5 g of thedesired isomer which was dissolved in ethyl acetate and added dropwiseto a stirred solution of anhydrous diethyl ether saturated withhydrochloric acid. The resulting white precipitate was collected byfiltration and dried to give 474 mg (79%) white solid: ¹H NMR (d⁶-DMSO,d): 1.47(m, 6H), 2.90(s, 3H), 2.95(s, 3H), 3.65(dd, J=9 Hz, 2H), 4.49(d,J=7.9 Hz, 2H), 4.73(m, 1H), 6.93(s, 1H), 7.18(s, 1H), 7.26(m, 6H),7.49(d, J=8.7 Hz, 1H), 7.60(m, 2H), 7.84(d, J=10.5 Hz, 1H), 7.98(m, 3H),8.14(d, J=9.4 Hz, 2H), 8.45(d, J=6.8 Hz, 1H), 10.74(bs, 1H). FAB+exactMS (M⁺+1): 557.2876 calculated, 557.2873 found Anal. (C₃₁H₃₉N₆O₄Cl₃):H,N,C: calcd, 56.01; found, 56.72.

EXAMPLES PART 2B

To a solution of m-anisaldehyde, 27.2 g (200 mmol) andbenzyltriethylammonium chloride, 2.46 g (10.8 mmol) stirring inchloroform (32 mL) at 56° C. was added sodium hydroxide (50 mL of 50%aqueous solution) dropwise over a period of 2 h keeping the temperaturebetween 54° C. and 58° C. After 1 h, the solution was cooled, thenpoured into an ice/water mixture. The resulting mixture was washed withether. The aqueous layers were acidified with 6 N sulfuric acid, thenextracted with ether. The organic extracts were washed with brine, driedover sodium sulfate, filtered, and concentrated to yield 36.4 g of anoil which was used without purification.

To a solution of the compound of Preparation 145 (36.4 g, 200 mmol)stirring in absolute ethanol (200 mL) was slowly added a solution ofconcentrated sulfuric acid (20 mL). The resulting mixture was heated toreflux for 5 h then cooled to ambient temperature, poured into anice/water mixture, and extracted with ether. The combined organicextracts were washed with saturated sodium bicarbonate and brine thendried over sodium sulfate and concentrated. The resulting material waspurificed by flash chromatography (silica gel, 15% ethylacetate/hexanes) to give 13.6 g (33% over the two steps) of the desiredproduct an oil: ¹H-NMR is consistent with structure.

To a solution of the product of Preparation 146 (4.0 g, 19 mmol)stirring in chloroform (50 mL) at 0° C. was added phosphorus tribromide(2.1 mL, 21 mmol). The reaction mixture was warmed to ambienttemperature and stirred for 5 h, then poured into an ice/water mixtureand extracted with chloroform. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography (silica gel, chloroform) toyield 3.9 g (75%) of the desired product as an oil: ¹H-NMR is consistentwith structure; MS (FD) 272, 274 (M+).

To a slurry of sodium hydride (0.86 g, 20 mmol) stirring indimethylformamide (30 mL) at room temperature was added 4-nitroimidazole(2.26 g, 20 mmol). The reaction was cooled to 0° C. and 3.9 g (19 mmol)of the product of Preparation 147 was added. After 16 g, the mixture wasslowly warming to ambient temperature. The reaction was poured into anice/water mixture and extracted with ethyl acetate. The combined organicextracts were washed with water, brine, dried over sodium sulfate, andconcentrated. The residue was purified by flash chromatography (silicagel, 40% ethyl acetate/hexanes) to yield 0.87 g (15%) of the desiredproduct: ¹H-NMR is consistent with structure; MS (ion spray) 306 (M+1);Anal. Calc'd for C₁₄H₁₅N₃O₅: C, 55.08; H, 4.95; N, 13.76. Found: C,55.63; H, 4.99; N, 12.98.

To a slurry of 10% palladium on carbon (2.26 g, 20 mmol) intetrahydrofuran was added a solution of the product of Preparation 148(1.21 g, 3.96 mmol) in tetrahydrofuran (20 mL). The mixture was reactedunder a hydrogen atmosphere (40 psi) on a Parr apparatus for 3 h andsubsequently filtered through celite. To this solution was added of theproduct of Preparation 1d (1.5 g, 3.96 mmol), 1-hydroxybenzotriazole(0.59 g, 4.35 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(0.9 g, 4.35 mmol). After 16 h, the reaction mixture was filtered andconcentrated. The resulting residue was purified by flash chromatography(silica gel, chloroform to 1% methanol/chloroform gradient) to yield2.24 g (89%) of the desired product: ¹H-NMR is consistent withstructure; MS (ion spray) 638.4 (M+1); Anal. Calc'd for C₃₃H₄₃N₅O₈: C,62.15; H, 6.80; N, 10.98. Found: C, 61.47; H, 6.41; N, 11.09.

To a solution of the product of Preparation 149 (2.19 g, 3.4 mmol)stirring in dioxane (50 mL) at room temperature was added a solution oflithium hydroxide (0.1 g, 4.08 mmol) in water (35 mL). After 15 min, thereaction was acidified to pH=3.0 with 1 N hydrochloric acid andextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated toyield 2.0 g (95%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (ion spray) 610 (M+1); Anal. Calc'd forC₃₁H₃₉N₅O₈.1.2dioxane: C, 60.10; H, 6.85; N, 9.79. Found: C, 59.78; H,6.58; N, 10.14.

To a solution of the product of Preparation 150 (0.6 g, 1.0 mmol) wasadded of 4-methylpiperidine (0.12 mL, 1.0 mmol), 1-hydroxybenzotriazole(0.15 g,1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(0.23 g, 1.1 mmol). After 16 h, the reaction mixture was concentrated,slurried in ethyl acetate and filtered. Water was added and the mixturewas extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue was purified by flash chromatography (silica gel, 4%methanol/chloroform) to yield 0.46 g (67%) of the desired product as awhite foam: ¹H-NMR is consistent with structure; MS (ion spray) 691.3(M+1) ; Anal. Calc'd for C₃₇H₅₀N₆O₇: C, 64.33; H, 7.29; N, 12.16. Found:C, 64.07; H, 7.29; N, 12.34.

Examples 63 and 64

To a solution of the product of Preparation 151 (0.37 g, 0.53 mmol)stirring in dichloromethane (6 mL) at room temperature was addedtrifluoroacetic acid (2 mL). After 1 h, the reaction mixture was pouredinto a solution of saturated sodium bicarbonate. The mixture wasextracted with chloroform. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered, and concentrated. Theresidue was dissolved in ethyl acetate and this solution was acidifiedwith a saturated solution of hydrochloric acid in ether. The resultingslurry was concentrated to yield 0.3 g (86%) of the desired product:¹H-NMR is consistent with structure; MS (ion spray) 591.6 (M+1); Anal.Calc'd for C₃₂H₄₂N₆O₅.2.2HCl: C, 57.29; H, 6.64; N, 12.53. Found: C,57.18; H, 6.54; N, 12.23. 0.14 g (0.2 mmol) of the free base was sentfor chiral separation. Resolution of the diastereomers by HPLC gave twoproducts:

Example 63. (Isomer 1). To the solution of the purified isomer in ethylacetate was added a saturated solution of hydrochloric acid in ether.The resulting slurry was concentrated to yield 0.04 g (28%) of thedesired isomer as a white solid: ¹H-NMR is consistent with structure;t_(R)=6.92 min; MS (high res) Calc'd for C₃₂H₄₃N₆O₅: 591.3295. Found:591.3299. Anal. Calc'd for C₃₂H₄₃N₆O₅.2.2HCl: C, 57.29; H, 6.64; N,12.53. Found: C, 57.29; H, 6.25; N, 12.37.

Example 64. (Isomer 2). To the solution of the purified isomer in ethylacetate was added a saturated solution of hydrochloric acid in ether.The resulting slurry was concentrated to yield 0.03 g (21%) of thedesired isomer as a tan foam: ¹H-NMR is consistent with structure;t_(R)=9.64 min; MS (high res) Calc'd for C₃₂H₄₃N₆O₅: 591.3295. Found:591.3288.

To a solution of the product of Preparation 150 (0.6 g, 1.0 mmol),pyrrolidine (0.8 mL, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),in dimethylformamide (20 mL) as described in Preparation 150 gave 0.42 g(64%) of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (ion spray) 663.4 (M+1); Anal. Calc'd for C₃₅H₄₆N₆O₇: C,63.43; H, 7.00; N, 12.68. Found: C, 63.39; H, 6.97; N, 12.58.

Example 65

To a solution of the product of Preparation 152 (0.35 g, 0.53 mol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as in described inExample 63 gave 0.23 g (68%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (ion spray) 563.5 (M+1); Anal.Calc'd for C₃₀H₃₈N₆O₅.2.3HCl: C, 55.73; H, 6.28; N, 13.00. Found: C,55.97; H, 6.18; N, 12.87.

To a solution of 2-anisaldehyde (13.5 g, 100 mmol),benzyltriethylamonium chloride (1.23 g, 5 mmol), chloroform (16 mL) and50% sodium hydroxide (25 mL) as described Preparation 145 gave 15.0 g ofthe desired product as an oil which was carried without furtherpurification.

To a solution of the product of Preparation (15.04 g, 83 mmol),concentrated sulfuric acid (10 mL) and absolute ethanol (100 mL) asdescribed in Preparation 146 gave 8.1 g (38% over the two steps) of thedesired product as an oil: ¹H-NMR is consistent with structure; MS (FD)210 (M+).

To a solution of the product of Preparation (4.0 g, 19 mmol), phosphorustribromide (2.05 mL, 20 mmol) and chloroform (50 mL) as described inPreparation 147 gave 4.9 g (95%) of the desired product: ¹H-NMR isconsistent with structure; MS (FD) 272, 274 (M+).

Reaction of the product of Preparation 155 (5.18 g, 19.0 mmol),4-nitroimidazole (2.37 g, 20.9 mmol) and sodium hydride (0.84 g, 20.9mmol) in dimethylformamide (50 mL) as described in Preparation 148 gave5.8 g (100%) of the desired product as a colorless oil which solidifiesupon standing: 1H-NMR is consistent with structure; MS (FD) 305 (M+);Anal. Calc'd for C₁₄H₁₅N₃O₅: C, 55.08; H, 4.95; N, 13.76. Found: C,54.87; H, 4.96; N, 13.47.

Reduction of the product of Preparation 156 (1.8 g, 5.8 mmol), 10%palladium on carbon (0.9 g) in tetrahydrofuran (80 mL) followed bycoupling with the product of Preparation 1d (2.2 g, 5.8 mmol),1-hydroxybenzotriazole (0.86 g, 6.4 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.3 g, 6.4 mmol), asdescribed in Preparation 149 gave 2.0 g (54%) of the desired compound asa tan foam: ¹H-NMR is consistent with structure; MS (FD) 637 (M+); Anal.Calc'd for C₃₃H₄₃N₅O₈.0.2H20: C, 61.80; H, 6.82; N, 10.92. Found: C,61.65; H, 6.93; N, 11.12.

Reaction of the product of Preparation 157 (1.95 g, 3.0 mmol) andlithium hydroxide (0.09 g, 3.6 mmol) in dioxane (40 mL) and water (20mL) as described in Preparation 150 gave 1.72 g (94%) of the desiredproduct as a white foam: ¹H-NMR is consistent with structure; MS (FD)610 (M+).

Reaction of the product of Preparation 158 (0.5 g, 0.82 mmol),4-methylpiperidine (0.1 mL, 0.82 mmol), 1-hydroxybenzotriazole (0.12 g,0.9 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.19 g,0.9 mmol) in dimethylformamide (40 mL) as described in Preparation 151gave 0.45 g (80%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 690 (M+); Anal. Calc'd forC₃₇H₅₀N₆O₇: C, 64.33; H, 7.30; N, 12.16. Found: C, 64.32; H, 7.21; N,11.97.

Example 66

Reaction of the product of Preparation 159 (0.4 g, 0.58 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 63 gave 0.3 g (79%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (high res) Calc'd forC₃₂H₄₃N₆O₅: 591.3295. Found: 591.3298. Anal. Calc'd for C₃₂H₄₂N₆O₅.2HCl:C, 57.92; H, 6.68; N, 12.66. Found: C, 57.27; H, 6.24; N, 11.82.

Reaction of the product of Preparation 158 (0.5 g, 0.82 mmol),pyrrolidine (0.07 mL), 1-hydroxybenzotriazole (0.12 g, 0.9 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.19 g, 0.9 mmol) indimethylformamide (40 mL as described in Preparation 151 gave 0.35 g(65%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 662 (M+); Anal. Calc'd for C₃₅H₄₆N₆O₇: C, 63.43; H,7.00; N, 12.68. Found: C, 63.26; H, 6.94; N, 12.43.

Example 67

Reaction of the product of Preparation 160 (0.3 g, 0.4 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 63 gave 0.24 g (96%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (high res) Calc'd forC₃₀H₃₉N₆O₅: 563.2982. Found: 563.2989. Anal. Calc'd forC₃₀H₃₈N₆O₅.2.4HCl: C, 55.42; H, 6.26; N, 12.93. Found: C, 55.51; H,6.10; N, 12.30.

Reaction of the product of Preparation 158 (0.5 g, 0.82 mmol),4-(4-fluorobenzoyl)piperidine hydrochloride (0.2 g, 0.82 mmol),triethylamine (0.13 mL, 0.9 mmol), 1-hydroxybenzotriazole (0.12 g, 0.9mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.19 g, 0.9mmol) in dimethylformamide (40 mL) as described in Preparation 151 gave0.41 g (62%) of the desired product as a white foam: ¹H-NMR isconsistent with structure; MS (FD) 799 (M+); Anal. Calc'd forC₄₃H₅₁FN₆O₈: C, 64.65; H, 6.43; N, 10.52. Found: C, 64.44; H, 6.56; N,10.53.

Example 68

Reaction of the product of Preparation 161 (0.36 g, 0.45 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (6 mL) as described inExample 63 gave 0.26 g (74%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 699 (M+); Anal. Calc'd forC₃₈H₄₃FN₆O₆.2HCl: C, 59.14; H, 5.88; N, 10.89. Found: C, 59.36; H, 5.99;N, 10.80.

Reaction of 3-tolylbenzaldehyde (12 g, 100 mmol), benzyltriethylammoniumchloride (1.23 g, 5 mmol), chloroform (16 mL) and 50% sodium hydroxide(25 mL) as described in Preparation 145 gave 16.2 g of an oil which wasused without further purification.

Reaction of the product of Preparation 162 (16.2 g, 98 mmol), conc.sulfuric acid (10 mL) and absolute ethanol (100 mL) as described inPreparation 146 gave 10.8 g (52% over the two steps) of the desiredproduct as an oil: ¹H-NMR is consistent with structure; MS (FD) 194(M+).

Reaction of the product of Preparation 163 (4.85 g, 25 mmol), phosphorustribromide (2.65 mL, 27.5 mmol) and chloroform (50 mL) as described inPreparation 147 gave 3.71 g (58%) of the desired product as an oil:1H-NMR is consistent with structure; MS (FD) 256 (M+).

Reaction of the product of Preparation 164 (3.7 g, 14.4 mmol),4-nitroimidazole (1.8 g, 15.9 mmol) and sodium hydride (0.64 g, 15.9mmol) in dimethylformamide (30 mL) as described in Preparation 148 gave3.2 g (77%) of the desired product as an oil: ¹H-NMR is consistent withstructure; MS (FD) 289 (M+); Anal. Calc'd for C₁₄H₁₅N₃O₄: C, 58.13; H,5.23; N, 14.52. Found: C, 58.18; H, 5.53; N, 14.89.

Reduction of the product of Preparation 164 (1.15 g, 4.0 mmol) 5%palladium on carbon (0.57 g) in tetrahydrofuran (30 mL) followed bycoupling with the product of Preparation 1d (1.5 g, 4.0 mmol),1-hydroxybenzotriazole (0.6 g, 4.4 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.9 g, 4.4 mmol) asdescribed in Preparation 149 gave 2.24 g (90%) of the desired product:¹H-NMR is consistent with structure; MS (FD) 621 (M+); Anal. Calc'd forC₃₃H₄₃N₅O₇: C, 63.75: H, 6.97; N, 11.26. Found: C, 63.69; H, 7.06; N,11.27.

Reaction of the product of Preparation 165 (2.0 g, 3.3 mmol) withlithium hydroxide (0.088 g, 3.64 mmol) in dioxane (20 mL) and water (10mL) as described in Preparation 150 gave 1.95 g (100%) of the desiredproduct: ¹H-NMR is consistent with structure; MS (FD) 594 (M+); Anal.Calc'd for C₃₁H₃₉N₅O₇.1H₂O: C, 61.59; H, 6.93; N, 10.38. Found: C,61.26; H, 6.86; N, 10.77.

Reaction of the product of Preparation 166 (0.6 g, 1.0 mmol), (0.7 g,4-(4-fluorobenzoyl)piperidine hydrochloride (0.24 g, 1.0 mmol),triethylamine (0.1 g, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol), in dimethylformamide (13 mL) as described in Preparation 151 gave0.7 g (90%) of the desired product: ¹H-NMR is consistent with structure;MS (FD) 782 (M+); Anal. Calc'd for C₄₃H₅₁FN₆O₇: C, 65.97; H, 6.57; N,10.73. Found: C, 66.01; H, 6.54; N, 10.52.

Examples 69 and 70

Reaction of the product of Preparation 167 (0.47 g, 0.6 mmol) withtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as describedExample 63 gave 0.44 g (98%) of the desired product as a foam: ¹H-NMR isconsistent with structure; MS (ion spray) 682.2 (M+1); Anal. Calc'd forC₃₈H₄₃FN₆O₅.2.55HCl: C, 59.22; H, 5.94; N, 10.90. Found: C, 58.84; H,5.94; N, 10.73. Resolution of the diastereomers (0.25 g, 0.37 mmol) bychiral HPLC gave the individual isomers:

Example 69. (Isomer 1) 0.069 g (27%) of the desired isomer as the freebase. ¹H-NMR is consistent with structure; t_(R)=5.2 min; MS (ion spray)683.4 (M+1).

Example 70. (Isomer 2) 0.065 g (26%) of the desired isomer as the freebase. ¹H-NMR is consistent with structure; t_(R)=6.5 min; MS (ion spray)683.4 (M+1); Anal. Calc'd for C₃₈H₄₃FN₆O₅.0.1H₂O: C, 63.48; H, 6.17; N,11.68. Found: C, 63.07; H, 6.07; N, 11.39.

Reaction of the product of Preparation 166 (0.59 g, 1.0 mmol),4-methylpiperidine (0.099 g, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g,1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (13 mL) as described in Preparation 151 gave0.67 g (100%) of the desired product as a foam: ¹H-NMR is consistentwith structure; MS (ion spray) 675 (M+1); Anal. Calc'd for C₂₇H₅₀N₆O₆:C, 65.85; H, 7.47; N, 12.45. Found: C, 66.09; H, 7.23; N, 12.53.

Examples 71 and 72

Reaction of the product of Preparation 168 (0.51 g, 0.76 mmol) withtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as described inExample 63 gave 0.42 g (86%) of the desired product: ¹H-NMR isconsistent with structure; MS (ion spray) 574.1 (M+1); Anal. Calc'd forC₃₂H₄₂N₆O₄.2.25HCl: C, 58.52; H, 6.79; N, 12.80. Found: C, 58.54; H,6.68; N, 12.80. Resolution of the diastereomers (0.173 g, 0.32 mmol) bychiral HPLC gave the individual isomers which were individually treatedwith a saturated solution of hydrochloric acid in diethyl ether to givethe desired products:

Example 71. (Isomer 1) ¹H-NMR is consistent with structure; t_(R)=6.22min; MS (ion spray) 575.4 (M+1); Anal. Calc'd for C₃₂H₄₂N₆O₄.2.3HCl: C,58.36; H, 6.78; N, 12.76. Found: C, 58.23; H, 6.57; N, 12.53.

Example 72. (Isomer 2) ¹H-NMR is consistent with structure; t_(R)=8.53min; MS (ion spray) 575.4 (M+1); Anal. Calc'd for C₃₂H₄₂N₆O₄.2.55HCl: C,57.56; H, 6.73; N, 12.59. Found: C, 57.95; H, 6.91; N, 12.29.

Reaction of the product of Preparation 166 (0.59 g, 1.0 mmol),pyrrolidine (0.071 g, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (13 mL) as described in Preparation 151 gave0.57 g (88%) of the desired product: ¹H-NMR is consistent withstructure; MS (ion spray) 646 (M+1); Anal. Calc'd for C₃₅H₄₆N₆O₆: C,65.00; H, 7.17; N, 12.99. Found: C, 64.95; H, 6.98; N, 13.19.

Example 73

Reaction of the product of Preparation 170 (0.55 g, 0.85 mmol) andtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as described inExample 63 gave 0.37 g (70%) of the desired product: ¹H-NMR isconsistent with structure; MS (ion spray) 546.1 (M+1); Anal. Calc'd forC₃₀H₃₈N₆O₄.2.4HCl: C, 56.79; H, 6.42; N, 13.24. Found: C, 56.81; H,6.35; N, 13.10.

Reaction of 2-methylbenzaldehyde (12.0 g, 100 mmol),triethylbenzylammonium chloride (1.23 g, 5 mmol), chloroform (16 mL) and50% sodium hydroxide (25 mL) as described in Preparation 145 gave 16.0of an oil which was used without further purification.

Reaction of the product of Preparation 170 (16.0 g, 96 mmol),concentrated sulfuric acid (10 mL)and absolute ethanol (100 mL) asdescribed in Preparation 146 gave 15.2 g (78% over the two steps) of thedesired product: ¹H-NMR is consistent with structure; MS (ion spray) 194(M+1).

Reaction of the product of Preparation 171 (3.88 g, 20 mmol), phosphorustribromide (2.2 mL, 22 mmol), chloroform (50 mL) as described inPreparation 147 gave 2.87 g (65%) of the desired product as a oil;¹H-NMR is consistent with structure; MS (ion spray) 256, 258 (M+).

Reaction of the product of Preparation 172 (3.3 g, 12.8 mmol),4-nitroimidazole (1.53 g, 13.5 mmol) and sodium hydride (0.32 g, 13.5mmol) in dimethylformamide (30 mL) as described in Preparation 148 gave3.1 g (84%) of the desired product as an oil: ¹H-NMR is consistent withstructure; MS (ion spray) 289 (M+1); Anal. Calc'd for C₁₄H₁₅N₃O₄: C,58.13; H, 5.23; N, 14.52. Found: C, 58.41; H, 5.26; N, 14.47.

Reduction of the product of Preparation 173 (1.15 g, 3.96 mmol) under ahydrogen atmosphere with 5% palladium on carbon (0.59 g) intetrahydrofuran (30 mL) followed by coupling with the product ofPreparation 1d (1.5 g, 3.96 mmol), 1-hydroxybenzotriazole (0.59 g, 4.35mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.9 g, 4.35 mmol)as described in Preparation 149 gave 2.43 g (99%) of the desired productas a foam: ¹H-NMR is consistent with structure; MS (ion spray) 621.2(M+1); Anal. Calc'd for C₃₃H₄₃N₅O₇: C, 63.75; H, 6.97; N, 11.26. Found:C, 63.59; H, 7.12; N, 11.38.

Reaction of the product of Preparation 174 (2.2 g, 3.6 mmol) withlithium hydroxide (0.096 g, 4.0 mmol) in dioxane (20 mL) and water (10mL) as described in Preparation 150 gave 2.1 g (100%) of the desiredproduct: ¹H-NMR is consistent with structure; MS (ion spray) 594 (M+1);Anal. Calc'd for C₃₁H₃₉N₅O₇.0.4H₂0: C, 61.27; H, 6.91; N, 10.57. Found:C, 60.93; H, 6.57; N, 10.92.

Reaction of the product of Preparation 175 (0.59 g, 1.0 mmol),4-methylpiperidine (0.099 g, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g,1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (10 mL) as described in Preparation 151 gavethe desired product as an oil: ¹H-NMR is consistent with structure; MS(ion spray) 674.3 (M+1); Anal. Calc'd for C₃₇H₅₀N₆O₆: C, 65.85; H, 7.47;N, 12.45. Found: C, 65.56; H, 7.53; N, 12.69.

Example 74

Reaction of the product of Preparation 176 (0.49 g, 0.72 mmol) withtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as described inExample 63 gave 0.31 g (75%) of the desired product: ¹H-NMR isconsistent with structure; MS (ion spray) 574 (M+1); Anal. Calc'd forC₃₂H₄₂N₆O₄.2HCl: C, 59.35; H, 6.85; N, 12.98. Found: C, 59.27; H, 6.76;N, 13.02.

Reaction of the product of Preparation 175 (0.59 g, 1.0 mmol),pyrrolidine (0.071 g, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (13 mL) as described in Preparation 151 gave0.51 g (79%) of the desired product: ¹H-NMR is consistent withstructure; MS (ion spray) 646.2 (M+1); Anal. Calc'd for C₃₅H₃₆N₆O₆: C,65.00; H, 7.17; N, 12.00. Found: C, 64.89; H, 7.15; N, 12.77.

Examples 75 and 76

Reaction of the product of Preparation 177 (0.40 g, 0.62 mmol) withtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as described inExample 63 gave 0.36 g (95%) of the desired product: ¹H-NMR isconsistent with structure; MS (ion spray) 546 (M+1); Anal. Calc'd forC₃₀H₃₈N₆O₄.2HCl: C, 58.16; H, 6.51; N, 13.56. Found: C, 58.09; H, 6.43;N, 13.60. Resolution of the diastereomers (0.17 g, 0.31 mmol) by chiralHPLC gave the respective isomers which were individually treated with asaturated solution of hydrochloric acid in diethyl ether to give thedesired products:

Example 75. (Isomer 1) 0.039 g (20%), ¹H-NMR is consistent withstructure; t_(R)=6.50 min; MS (ion spray) 547.2 (M+1); Anal. Calc'd forC₃₀H₃₈N₆O₄.2.3HCl: C, 57.15; H, 6.44; N, 13.33. Found: C, 57.15; H,6.17; N, 12.94.

Example 76. (Isomer 2) 0.054 g (28%) of the desired isomer as thehydrochloric acid salt. ¹H-NMR is consistent with structure; t_(R)=7.52min; MS (ion spray) 547.2 (M+1); Anal. Calc'd for C₃₀H₃₈N₆O₄.2.75HCl: C,55.70; H, 6.35; N, 12.99. Found: C, 55.68; H, 6.35; N, 12.66.

Reaction of the product of Preparation 175 (0.59 g, 1.0 mmol),4-(4-fluorobenzoyl)piperidine hydrochloride (0.24 g, 1.0 mmol),triethylamine (0.11 g, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (13 mL) as described in Preparation 151 gave0.58 g (82%) of the desired product as a product: ¹H-NMR is consistentwith structure; MS (ion spray) 783 (M+1); Anal. Calc'd for C₄₃H₅₁FN₅O₇:C, 65.97; H, 6.57; N, 10.73. Found: C, 65.70; H, 6.69; N, 10.47.

Example 77

Reaction of the product of Preparation 178 (0.58 g, 0.74 mmol) withtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as described inExample 63 gave 0.52 g (93%) of the desired product: ¹H-NMR isconsistent with structure; MS (ion spray) 682 (M+1); Anal. Calc'd forC₃₈H₄₃FN₆O₅.2HCl: C, 60.40; H, 6.00; N, 11.12; Cl, 9.38. Found: C,60.35; H, 5.96; N, 11.17; Cl, 9.23.

To a solution of 4-methylphenylacetic acid, (7.5 g, 50 mmol) in carbontetrachloride (10 mL) was added thionyl chloride (14.4 mL, 200 mmol).The reaction was heated to reflux. After 30 min, the mixture was cooledto 20° C. and a solution of N-bromosuccinimde (8.9 g, 50 mmol) and HBr(8 drops of a 48% aqueous solution) in carbon tetrachloride (15 mL). Thereaction was heated to reflux and after 30 min, cooled to ambienttemperature, filtered and concentrated. The resulting oil was added toabsolute ethanol at 0° C. and then concentrated. The residue waspurified by flash chromatography (silica gel, 3% ethyl acetate/hexanes)to yield 5.1 g (40%) of the desired product as an oil: ¹H-NMR isconsistent with structure; MS (FD) 258 (M+); Anal. Calc'd forC₁₁H₁₃BrO₂.1.3CHCl₃: C, 44.44; H, 4.34. Found: C, 44.58; H, 4.51.

Reaction of the product of Preparation 179 (5.0 g, 19.5 mmol),4-nitroimidazole (2.2 g, 19.5 mmol) and sodium hydride (0.47 g, 19.5mmol) indimethylformamide (50 mL) as described in Preparation 148 gave1.9 g (33%) of the desired product as a yellow oil: ¹H-NMR is consistentwith structure; MS (FD) 289 (M+); Anal. Calc'd for C₁₄H₁₅N₃O₄: C, 58.13;H, 5.23; N, 14.52. Found: C, 58.33; H, 5.17; N, 14.70.

Reduction of the product of Preparation 180 (4.9 g, 17.0 mmol) under ahydrogen atmosphere with 10% palladium on carbon (3.5 g) intetrahydrofuran (120 mL) followed by coupling of the product ofPreparation 1d (6.43 g, 17.0 mmol), 1-hydroxybenzotriazole (2.6 g, 18.7mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.9 g, 18.7 mmol)as described in Preparation 149 gave 6.54 g (62%) of the desiredcompound as an orange foam: ¹H-NMR is consistent with structure; MS (ionspray) 622.5 (M+1); Anal. Calc'd for C₃₃H₄₃N₅O₇: C, 63.75; H, 6.97; N,11.26. Found: C, 63.80; H, 7.09; N, 11.36.

Reaction of the product of Preparation 181 (6.49 g, 10.0 mmol) withlithium hydroxide (0.3 g, 12.0 mmol)in dioxane (90 mL) and water (50 mL)as described in Preparation 150 gave 5.93 g (100%) of the desiredproduct: ¹H-NMR is consistent with structure; MS (ion spray) 594.6(M+1); Anal. Calc'd for C₃₁H₃₉N₅O₇.0.4 dioxane: C, 62.26; H, 6.76; N,11.14. Found: C, 62.33; H, 6.41; N, 11.19.

Reaction of the product of Preparation 182 (5.0 g, 8.4 mmol),4-methylpiperidine (1.0 mL, 8.4 mmol), 1-hydroxybenzotriazole (1.3 g,9.24 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.9 g,9.24 mmol) in dimethylformamide (80 mL) as described in Preparation 151gave 4.44 g (78%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (ion spray) 675.7 (M+1); Anal. Calc'd forC₃₇H₅₀N₆O₆.0.3H₂0: C, 65.33; H, 7.50; N, 12.35. Found: C, 65.28; H,7.37; N, 12.30.

Examples 78 and 79

Reaction of the product of Preparation 183 (4.17 g, 6.4 mmol)andtrifluoroacetic acid (20 mL) in dichloromethane (50 mL) as described inExample 63 gave 2.59 g (65%) of the desired product: ¹H-NMR isconsistent with structure; MS (ion spray) 575.5 (M+1). Resolution of thediastereomers (0.22 g, 0.34 mmol) by chiral HPLC gave the respectiveisomers which were individually treated with a saturated solution ofhydrochloric acid in diethyl ether to give the desired products:

Example 78. (Isomer 1): 0.091 g (36%), ¹H-NMR is consistent withstructure; t_(R)=4.40 min; MS (ion spray) 575.3 (M+1); Anal. Calc'd forC₃₂H₄₂N₆O₄: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.30; H, 7.20; N,14.40.

Example 79. (Isomer 2): 0.059 g (24%); ¹H-NMR is consistent withstructure; t_(R)=5.3 min; MS (ion spray) 575.3 (M+1); Anal. Calc'd forC₃₂H₄₂N₆O₄: C, 66.88; H, 7.37; N, 14.62. Found: C, 67.02; H, 7.34; N,14.40.

Reaction of the product of Preparation 182 (0.7 g, 1.2 mmol),dimethylamine hydrochloride (0.1 g, 1.2 mmol), triethylamine (0.2 mL,1.32 mmol), 1-hydroxybenzotriazole (0.18 g, 1.32 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.32 mmol) indimethylformamide (30 mL) as described in Preparation 151 gave 0.55 g(75%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (ion spray) 621.7 (M+1); Anal. Calc'd for C₃₃H₄₄N₆O₆: C,63.85; H, 7.15; N, 13.54. Found: C, 63.56; H, 7.37; N, 13.35.

Example 80

Reaction of the product of Preparation 184 (0.46 g, 0.74 mmol) withtrifluoroacetic acid (2 mL)in dichloromethane (6 mL) as described inExample 63 gave 0.22 g (50%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (ion spray) 521.4 (M+1); Anal.Calc'd for C₂₈H₃₆N₆O₄.2.5HCl: C, 54.97; H, 6.34; N, 13.74. Found: C,54.85; H, 6.23; N, 13.58.

Reaction of the product of Preparation 182 (0.59 g, 1 mmol), pyrrolidine(0.078 g, 1.1 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.1 mmol) indimethylformamide (12 mL) as described in Preparation 151 gave 0.52 g(80%) of the desired product: ¹H-NMR is consistent with structure; MS(ion spray) 646 (M+1); Anal. Calc'd for C₃₅H₄₆N₆O₆: C, 65.00; H, 7.17;N, 12.99. Found: C, 65.00; H, 7.05; N, 12.82.

Example 81

Reaction of the product of Preparation 185 (0.39 g, 0.61 mmol) withtrifluoroacetic acid (3.5 mL) indichloromethane (12 mL) as described inExample 63 gave 0.3 g (90%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (ion spray) 546 (M+1); Anal.Calc'd for C₃₀H₃₆N₆O₄.1.4HCl: C, 60.99; H, 6.69; N, 14.22. Found: C,61.08; H, 6.51; N, 13.89.

Reaction of the product of Preparation 182 (0.7 g, 1,32 mmol),4-(4-fluorobenzoyl)piperidine hydrochloride (0.3 g, 1.2 mmol),triethylamine (0.2 mL, 1.32 mmol), 1-hydroxybenzotriazole (0.18 g, 1.32mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.32mmol) in dimethylformamide (30 mL) as described in Preparation 151 gave0.68 g (72%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (ion spray) 783.6 (M+1); Anal. Calc'd forC₄₃H₅₁FN₆O₇: C, 65.97; H, 6.57; N, 10.73. Found: C, 65.86; H, 6.62; N,10.62.

Examples 82 and 83

Reaction of the product of Preparation 186 (0.7 g, 0.89 mmol) withtrifluoroacetic acid (2 mL) in dichloromethane (6 mL), as in Example 63from Examples Part 2A. 0.45 g (66%) of the desired product as a yellowsolid: ¹H-NMR is consistent with structure; MS (ion spray) 683.4 (M+1);Anal. Calc'd for C₃₈H₄₃N₆O₅.2.4HCl: C, 59.25; H, 5.94; N, 10.91. Found:C, 59.24; H, 5.66; N, 11.09. Resolution of the diastereomers (0.21 g,0.32 mmol) by chiral HPLC gave the respective isomers which wereindividually treated with a saturated solution of hydrochloric acid indiethyl ether to give the desired products:

Example 82. (Isomer 1) 0.092 g (38%); ¹H-NMR is consistent withstructure; t_(R)=5.83 min; MS (ion spray) 683.4 (M+1); Anal. Calc'd forC₃₈H₄₃FN₆O₅.2HCl: C, 60.40; H, 6.00; N, 11.12. Found: C, 60.11; H, 6.12;N, 10.98.

Example 83 (Isomer 2) 0.065 g (27%) of the desired isomer as a whitesolid: ¹H-NMR is consistent with structure; t_(R)=7.62 min; MS (ionspray) 683.4 (M+1); Anal. Calc'd for C₃₈H₄₃FN₆O₅.2HCl: C, 60.40; H,6.00; N, 11.12. Found: C, 60.15; H, 5.82; N, 10.96.

Reaction of 1-naphthylacetic acid (9.3 g, 50 mmol), thionyl chloride(14.4 mL, 200 mmol), carbon tetrachloride (35 mL), N-bromosuccinimide(8.9 g, 50 mmol), 48% HBr (8 drops) as described in Preparation 179 gave12.6 g (86%) of the desired product as an oil: ¹H-NMR is consistent withstructure.

Reaction of the product of Preparation 187 (11.8 g, 40 mmol),4-nitroimidazole (4.5 g, 40 mmol) and sodium hydride (1.6 g, 40 mmol) indimethylformamide (50 mL) as described in Preparation 148 gave 6.03 g(50%) of the desired product as an oil: ¹H-NMR is consistent withstructure; MS (ion spray) 325.1 (M+1); Anal. Calc'd forC₁₇H₁₅N₃O₄.0.37H₂O: C, 61.50; H, 4.78; N, 12.66. Found: C, 61.46; H,4.60; N, 12.73.

Reduction of the product of Preparation 188 (1.28 g, 4.0 mmol) under ahydrogen atmosphere with 5% palladium on carbon (0.6 g) followed bycoupling with the product of Preparation 1d (1.5 g, 4.0 mmol),1-hydroxybenzotriazole (0.59 g, 4.35 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.9 g, 4.35 mmol) intetrahydrofuran (30 mL) as described in Preparation 149 gave 1.99 g(77%) of the desired product as an orange foam: ¹H-NMR is consistentwith structure; MS (ion spray) 657 (M+1); Anal. Calc'd for C₃₆H₄₃N₅O₇:C, 65.74; H, 6.59; N, 10.65. Found: C, 65.67; H, 6.53; N, 10.87.

The product of Preparation 189 (1.97 g, 3.0 mmol), lithium hydroxide(0.08 g, 3.3 mmol), dioxane (20 mL), water (10 mL), as in Preparation150. 1.8 g (95%) of the desired product. ¹H-NMR is consistent withstructure; MS (ion spray) 630 (M+1); Anal. Calc'd forC₃₄H₃₉N₅O₇.1.05H₂0: C, 62.96; H, 6.39; N, 10.80. Found: C, 63.09; H,6.39; N, 10.40.

Reaction of the product of Preparation 190 (0.63 g, 1.0 mmol),4-methylpiperidine (0.099 g, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g,1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (12 mL) as described in Preparation 151 gave0.60 g (85%) of the desired material as a white solid: ¹H-NMR isconsistent with structure; MS (ion spray) 710 (M+1); Anal. Calc'd forC₄₀H₅₀N₆O₆: C, 67.58; H, 7.09; N, 11.82. Found: C, 67.33; H, 6.94; N,11.58.

Example 84

Reaction of the product of Preparation 191 (0.60 g, 0.84 mmol) withtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as described inExample 63 gave 0.47 g (92%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (ion spray) 610 (M+1); Anal.Calc'd for C₃₅H₄₂N₆O₄.2.7HCl: C, 59.28; H, 6.35; N, 11.85. Found: C,59.34; H, 6.57; N, 11.75.

Reaction of the product of Preparation 190 (0.63 g, 1.0 mmol),pyrrolidine (0.071 g, 1.0 mmol), 1-hydroxybenzotriazole(0.15 g, 1.1mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol) in dimethylformamide (12 mL) as described in Preparation 151 gave0.54 g (78%) of the desired product as a solid: ¹H-NMR is consistentwith structure; MS (ion spray) 682 (M+1); Anal. Calc'd for C₃₈H₄₆N₆O₆:C, 66.84; H, 6.79; N, 12.31. Found: C, 66.59; H, 6.78; N, 12.29.

Example 85

Reaction of the product of Preparation 192 (0.443 g, 0.65 mmol) withtrifluoroacetic acid (4 mL) in dichloromethane (12 mL) as described inExample 63 gave 0.27 g (65%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (ion spray) 582 (M+1); Anal.Calc'd for C₃₃H₃₈N₆O₄.2.8HCl: C, 57.88; H, 6.01; N, 12.27. Found: C,57.83; H, 6.47; N, 12.11.

To a solution of Preparation 8 from Examples Part 1 (1.0 g, 1.7 mmol),N,N-dimethylamine hydrochloride, 0.14 g (1.7 mmol), triethylamine, 0.26mL (1.9 mol) and 1-hydroxybenzotriazole, 0.26 g (1.9 mmol) in 70 mL ofdimethylformamide was added 0.4 g (1.9 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction mixture wasstirred overnight then concentrated. The residue was slurried in ethylacetate, filtered and water was added. The mixture was extracted withethyl acetate. The combined organic extracts were washed with brine,dried over sodium sulfate, filtered and concentrated. The residue waschromatographed on silica gel using 4% methanol/chloroform as eluant toyield 0.58 g (56%) of the desired compound as a white foam: ¹H-NMR isconsistent with structure; MS (FD) 606 (M+); Anal. Calc'd forC₃₂H₄₂N₆O₆: C, 63.35; H, 6.98; N, 13.85. Found: C, 63.18; H, 7.03; N,13.84.

Example 86

To a solution of the product of Preparation 193, 0.5 g (0.82 mmol) in 12mL of dichloromethane was added 4 mL of trifluoroacetic acid. Afterstirred for 1 h, water was added. The reaction was quenched with solidsodium bicarbonate and was extracted with chloroform. The combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered and concentrated. The residue was dissolved in ethyl acetateand hydrochloric acid-saturated ether was added. The resulting slurrywas concentrated to yield 0.4 g (85%) of the desired product as a yellowsolid: ¹H-NMR is consistent with structure; MS (FD) 506.4 (M+); Anal.Calc'd for C₂₇H₃₄N₆O₄.2.9HCl: C, 53.85; H, 4.50; N, 13.95. Found: C,53.91; H, 6.14; N, 13.76.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), diethylamine (0.18 mL, 1.7 mmol), 1-hydroxybenzotriazole(0.26 g, 1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4g, 1.9 mmol), dimethylformamide (80 mL) as described in Preparation 193gave 0.53 g (49%) of the desired product as a yellow foam: ¹H-NMR isconsistent with structure; MS (FD) 634.3 (M+).

Example 87

Reaction of the product of Preparation 194 (0.52 g, 0.82 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.47 g (100%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 534.1 (M+); Anal. Calc'dfor C₂₉H₃₈N₆O₄.2.4HCl: C, 55.99; H, 6.54; N, 13.51. Found: C, 55.88; H,6.91; N, 13.32.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), N,N-methylethylamine (0.15 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (40 mL) as in Preparation 193 gave 0.56 g (56%) of thedesired product as a tan foam: ¹H-NMR is consistent with structure; MS(FD) 620 (M+); Anal. Calc'd for C₃₃H₄₄N₆O₆: C, 63.85; H, 7.15; N, 13.54.Found: C, 63.45; H, 7.19; N, 13.15.

Example 88

(0.4 g, 0.64 mmol), trifluoroacetic acid (2 mL), dichloromethane (6 mL),as in Example 86 gave 0.32 g (84%) of the desired product as a yellowsolid: ¹H-NMR is consistent with structure; MS (FD) 520 (M+); Anal.Calc'd for C₂₈H₃₆N₆O₄.2.2HCl: C, 55.97; H, 6.41; N, 13.99. Found: C,56.11; H, 6.23; N, 13.60.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), cyclopropylamine (0.07 mL, 1.0 mmol), 1-hydroxybenzotriazole(0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23g, 1.1 mmol), dimethylformamide (30 mL) as described in Preparation 193gave 0.31 g (50%) of the desired product as a white foam: ¹H-NMR isconsistent with structure; MS (ion spray) 619.6 (M+1); Anal. Calc'd forC₃₃H₄₂N₆O₆.1.1H₂O: C, 62.07; H, 6.98; N, 13.15. Found: C, 62.19; H,6.43; N, 12.82.

Example 89

Reaction of the product of Preparation 196 (0.31 g, 0.5 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inexample 86 gave 0.27 g (90%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (ion spray) 518 (M+1); Anal.Calc'd for C₂₈H₃₄N₆O₄.2.4HCl: C, 55.49; H, 6.05; N, 13.87. Found: C,55.63; H, 5.27; N, 13.29.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), benzylamine (0.2 mL, 1.7 mmol), 1-hydroxybenzotriazole (0.26g, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9mmol), dimethylformamide (80 mL) as in Preparation 193 gave 0.86 g (75%)of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (FD) 669 (M+).

Example 90

Reaction of the product 197 (0.76 g, 1.1 mmol), trifluoroacetic acid (4mL), dichloromethane (12 mL) as described in Example 86 gave 0.52 g(79%) of the desired product as a yellow solid: ¹H-NMR is consistentwith structure; MS (FD) 568 (M+); Anal. Calc'd for C₃₂H₃₅N₆O₄.2.5HCl: C,58.25; H, 5.88; N, 12.74. Found: C, 57.95; H, 6.02; N, 13.18.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), N,N-benzylmethylamine (0.22 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL) as in Preparation 193 gave 0.65 g (56%) of thedesired product as a white foam: ¹H-NMR is consistent with structure; MS(FD) 682.5 (M+).

Example 91

Reaction of the product of Preparation 198 (0.6 g, 0.88 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.53 g (96%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 582.2 (M+); Anal. Calc'dfor C₃₃H₃₇N₆O₄.2.5HCl: C, 58.82; H, 6.08; N, 12.47. Found: C, 58.85; H,6.27; N, 12.39.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), methoxypropylamine (0.18 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (40 mL) as in Preparation 193 gave 0.8 g (73%) of thedesired product as a white foam: ¹H-NMR is consistent with structure; MS(FD) 650 (M+).

Example 92

Reaction of the product of Preparation 199 (0.75 g (1.16 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.52 g (72%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 550 (M+); Anal. Calc'd forC₂₉H₃₈N₆O₅.2.7HCl: C, 53.66; H, 6.32; N, 12.95. Found: C, 53.93; H,6.27; N, 13.14.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 2-(ethylthio)ethylamine hydrochloride (0.15 g, 1.0 mmol),triethylamine (0.16 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (30 mL) as in Preparation 193 gave 0.42 g (63%) of thedesired product as a white foam: ¹H-NMR is consistent with structure; MS(FD) 663.3 (M+); Anal. Calc'd for C₃₄H₄₆N₆O₆S: C, 61.24; H, 6.95; N,12.60. Found: C, 61.00; H, 6.83; N, 12.48.

Example 93

Reaction of the product of Preparation 200 (0.36 g, 0.54 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86 gave 0.28 g (80%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 566 (M+); Anal. Calc'd forC₂₉H₃₈N₆O₄S.2.2HCl: C, 53.84; H, 6.26; N, 12.99. Found: C, 53.99; H,6.03; N, 12.79.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), phenoxyethylamine (0.14 g, 1.0 mmol), 1-hydroxybenzotriazole(0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23g, 1.1 mmol), dimethylformamide (20 mL) as described in Preparation 193gave 0.53 g (76%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 698 (M+).

Example 94

Reaction of the product of Preparation 201 (0.46 g, 0.67 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.28 g (62%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 598 (M+); Anal. Calc'd forC₃₃H₃₈N₆O₅.2.0HCl: C, 59.01; H, 6.00; N, 12.51. Found: C, 58.97; H,6.09; N, 12.40.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-fluorophenethylamine (0.13 mL, 1.0 mmol),1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (30 mL) as described in Preparation 193 gave 0.5 g(71%) of the desired product as a yellow foam: ¹H-NMR is consistent withstructure; MS (FD) 700.5 (M+); Anal. Calc'd for C₃₈H₄₅FN₆O₆.0.5H₂O: C,64.30; H, 6.53; N, 11.84. Found: C, 64.12; H, 6.38; N, 11.73.

Example 95

Reaction of the product of Preparation 202 (0.5 g, 0.71 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86 gave 0.28 g (58%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 600 (M+); Anal. Calc'd forC₃₃H₃₇FN₆O₄.2.2HCl: C, 58.21; H, 5.80; N, 12.34. Found: C, 58.32; H,5.92; N, 12.07.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 3-pyrroline (0.13 mL, 1.7 mmol), 1-hydroxybenzotriazole (0.25g, 1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9mmol), dimethylformamide (80 mL) as described in Preparation 193 gave0.75 g (70%) of the desired product as a white foam: ¹H-NMR isconsistent with structure; MS (FD) 630.2 (M+).

Example 96

Reaction of the product of Preparation 203 (0.7 g, 1.1 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.52 g (84%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 530 (M+). Anal. Calc'd forC₂₉H₃₃N₆O₄.2.7HCl: C, 55.37; H, 5.88; N, 13.36. Found: C, 55.49; H,5.95; N, 13.56.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), R-2-methoxymethylpyrrolidine (0.2 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL), as described in Preparation 193 gave 0.82 g(71%) of the desired compound as a white foam: ¹H-NMR is consistent withstructure; MS (FD) 676.4 (M+).

Example 97

Reaction of the product of Preparation 204 (0.7 g, 1.0 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86 gave 0.56 g (92%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 576 (M+); Anal. Calc'd forC₃₁H₃₉N₆O₅.2.5HCl: C, 55.75; H, 6.41; N, 12.58. Found: C, 55.45; H,6.36; N, 13.17.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), D-proline methyl ester (0.22 g, 1.7 mmol),1-hydroxybenzotriazole (0.23 g, 1.7 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dichloromethane (50 mL) as described in Example 86 gave 0.2 g (17%) ofthe desired compound as a yellow foam: ¹H-NMR is consistent withstructure; MS (FD) 690 (M+).

Example 98

Reaction of the product of Preparation 205 (0.18 g, 0.26 mmol),trifluoroacetic acid (3.3 mL), dichloromethane (10 mL) as described inExample 86 gave 0.16 g (93%) of the desired product as a white foam:1H-NMR is consistent with structure; MS (FD) 590 (M+).

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), (S)-2-methoxymethylpyrrolidine (0.2 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL) as described in Preparation 193 gave 0.87 g(76%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 676 (M+).

Example 99

Reaction of the product of Preparation 206 (0.77 g, 1.1 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.54 g (77%) of the desired product as a tan solid:¹H-NMR is consistent with structure; MS (FD) 576.1 (M+); Anal. Calc'dfor C₃₁H₃₉N₆O₅.2.3HCl: C, 56.37; H, 6.45; N, 12.72. Found: C, 56.28; H,6.04; N, 13.36.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 3,5-dimethylpyrrolidine (0.2 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL), as described in Preparation 193 gave 0.95 g(85%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 661 (M+); Anal. Calc'd for C₃₆H₄₈N₆O₆: C, 65.43; H,7.32; N, 12.72. Found: C, 65.22; H, 7.19; N, 12.87.

Example 100

Reaction of the product of Preparation 208 (0.9 g, 1.4 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.69 g (83%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 561 (M+); Anal. Calc'd forC₃₁H₃₉N₆O₄.2.2HCl: C, 58.10; H, 6.64; N, 13.11. Found: C, 58.04; H,6.75; N, 13.53.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), azetidine (0.11 mL, 1.7 mmol), 1-hydroxybenzotriazole (0.26g, 1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9mmol), dimethylformamide (80 mL) as described in Preparation 193 gave0.64 g (61%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 618 (M+).

Example 101

Reaction of the product of Preparation 209 (0.5 g, 0.81 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.42 g (93%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 518 (M+); Anal. Calc'd forC₂₈H₃₃N₆O₄.2.5HCl: C, 55.15; H, 6.03; N, 13.78. Found: C, 55.36; H,5.87; N, 14.01.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), heptamethyleneimine (0.22 mL, 1-hydroxybenzotriazole (0.26 g,1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9mmol), dimethylformamide (80 mL) as described in Preparation 193 gave0.89 g (77%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 674 (M+); Anal. Calc'd for C₃₇H₅₀N₆O₆.0.6H₂O: C,64.82; H, 7.53; N, 12.26. Found: C, 64.59; H, 7.39; N, 12.83.

Example 102

Reaction of the product of Preparation 210 (0.83 g, 1.2 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.67 g (92%) of the desired product as a tan solid:¹H-NMR is consistent with structure; MS (high res) calc'd forC₃₂H₄₃N₆O₄: 575.3346. Found: 575.3352.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 3-azabicyclo(3.2.2)nonane (0.21 g, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL) as described in Preparation 193 gave 1.0 g(85%) of the desired compound as a yellow foam: ¹H-NMR is consistentwith structure; MS (FD) 686 (M+); Anal. Calc'd for C₃₈H₅₀N₆O₆: C, 66.45;H, 7.34; N, 12.24. Found: C, 66.65; H, 7.42; N, 12.34.

Example 103

Reaction of the product of Preparation 211 (0.95 g, 1.4 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.75 g (86%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 586 (M+); Anal. Calc'd forC₃₃H₄₁N₆O₄.2.2HCl: C, 59.43; H, 6.68; n, 12.60. Found: C, 59.54; H,6.86; N, 12.73.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), thiazolidine (0.134 mL, 1.7 mmol), 1-hydroxybenzotriazole(0.26 g, 1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4g, 1.9 mmol), dimethylformamide (40 mL) as described in Preparation 193gave 0.33 g (30%) of the desired product as a white foam: ¹H-NMR isconsistent with structure; MS (FD) 650 (M+).

Example 104

Reaction of the product of Preparation 212 (0.31 g, 0.48 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.28 g (93%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 550 (M+); Anal. Calc'd forC₂₈H₃₄N₆O₄S.2.6HCl: C, 52.10; H, 5.72; N, 13.01. Found: C, 52.01; H,5.78; N, 13.23.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), thiomorpholine (0.1 mL, 1.0 mmol), 1-hydroxybenzotriazole(0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23g, 1.1 mmol), dimethylformamide (40 mL) as described in Preparation 193gave 0.34 g (55%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 664 (M+); Anal. Calc'd forC₃₄H₄₄N₆O₆S.0.1H₂O: C, 61.43; H, 6.67; N, 12.64. Found: 59.81; H, 6.79;N, 12.31.

Example 105

Reaction of the product of Preparation 213 (0.3 g, 0.45 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.26 g (100%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 564.1 (M+); Anal. Calc'dfor C₂₉H₃₆N₆O₅.3HCl: C, 51.67; H, 5.83; N, 12.47. Found: C, 52.08; H,6.24; N, 12.48.

To a solution of the product of Preparation 213, 0.52 g (0.78 mmol) in10 mL of dichloromethane was added 0.36 mL (3.12 mmol) of 30% hydrogenperoxide. The solution was heated to reflux for 4 h, then quenched withsodium bisulfite and concentrated. The residue was chromatographed onsilica gel using 10% methanol/chloroform as eluant to yield 0.16 g (30%)of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (FD) 681 (M+); Anal. Calc'd for C₃₄H₄₄N₆O₇S.1.5H₂O: C,56.42; H, 6.54; N, 11.61. Found: C, 56.39; H, 6.15; N, 11.67.

Example 106

Reaction of the product of Preparation 214 (0.15 g, 0.21 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.13 g (100%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 580 (M+); Anal. Calc'd forC₂₉H₃₆N₆O₅S.2.5HCl: C, 51.84; H, 5.78; N, 12.51. Found: C, 51.81; H,5.79; N, 11.84.

Reaction of the product of Preparation 8 from Examples Part 1 (0.5 g,0.9 mmol), N-methylpiperazine (0.1 mL, 0.9 mmol), 1-hydroxybenzotriazole(0.13 g, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.2g, 1.0 mmol), dimethylformamide (30 mL) as described in Preparation 193gave 0.12 g (20%) of the desired product as a clear oil: ¹H-NMR isconsistent with structure; MS (FD) 662 (M+).

Example 107

Reaction of the product of Preparation 215 (0.1 g, 0.15 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.085 g (94%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 561 (M+).

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 1-acetylpiperazine (0.13 g, 1.0 mmol), 1-hydroxybenzotriazole(0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23g, 1.1 mmol), dimethylformamide (40 mL) as described in Preparation 193gave 0.52 g (75%) of the desired compound as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 689.4 (M+).

Example 108

Reaction of the product of Preparation 216 (0.47 g, 0.68 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.2 g (50%) of the desired product as a tan solid:¹H-NMR is consistent with structure; MS (FD) 589.3 (M+); Anal. Calc'dfor C₃₁H₃₉N₇O₅.4.5HCl: C, 49.40; H, 5.82; N, 13.01. Found: C, 49.84; H,5.99; N, 12.57.

Reaction of the product of Preparation 8 from Examples Part 1 (0.5 g,0.9 mmol), N-phenylpiperazine (0.14 mL, 0.9 mmol),1-hydroxybenzotriazole (0.13 g, 1.0 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.2 g, 1.0 mmol),dimethylformamide (30 mL) as described in Preparation 193 gave 0.42 g(65%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 723.7 (M+); Anal. Calc'd for C₄₀H₄₉N₇O₆: C, 66.37; H,6.82; N, 13.55. Found: C, 62.92; H, 6.87; N, 13.24.

Example 109

Reaction of the product of Preparation 217 (0.38 g, 0.5 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.2 g (87%) of the desired product as a tan foam: ¹H-NMRis consistent with structure; MS (FD) 623 (M+).

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 1-(4-fluorophenyl)piperazine (0.18 g, 1.0 mmol),1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (30 mL) as described in Preparation 193 gave 0.42 g(57%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 742 (M+); Anal. Calc'd for C₄₀H₄₈N₇O₆F.0.4H₂O: C,64.14; H, 6.57; N, 13.09. Found: C, 64.06; H, 6.35; N, 12.75.

Example 110

Reaction of the product of Preparation 218 (0.37 g, 0.5 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.36 g (100%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 641 (M+); Anal. Calc'd forC₃₅H₄₀N₇O₄F.2.8HCl: C, 56.52; H, 5.80; N, 13.18. Found: C, 56.92; H,5.79; N, 12.86.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-piperazinoacetophenone (0.2 g, 1.0 mmol),1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (30 mL) as described in Preparation 193 gave 0.42 g(55%) of the desired compound as a tan foam: ¹H-NMR is consistent withstructure; MS (ion spray) 766.2 (M+1); Anal. Calc'd forC₄₂H₅₂N₇O₇.0.8H₂O: C, 64.56; H, 6.91; N, 12.55. Found: C, 64.59; H,6.59; N, 12.31.

Example 111

Reaction of the product of Preparation 219 (0.36 g, 0.47 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.33 g (94%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (ion spray) 666 (M+1); Anal.Calc'd for C₃₇H₄₃N₇O₅.2.5HCl: C, 58.71; H, 6.06; N, 12.95. Found: C,58.56; H, 6.44; N, 12.60.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 1-(2-pyridyl)piperazine (0.16 mL, 1.0 mmol),1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (40 mL) as described in Preparation 193 gave 0.48 g(66%) of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (ion spray) 725 (M+1); Anal. Calc'd for C₃₉H₄₈N₈O₇.0.5H₂O:C, 63.83; H, 6.73; N, 15.27. Found: C, 63.85; H, 6.76; N, 15.09.

Example 112

Reaction of the product of Preparation 220 (0.42 g, 0.58 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.35 g (88%) of the desired product as a white foam:¹H-NMR is consistent with structure; MS (high res) calc'd forC₃₄H₄₁N₃O₄: 625.3251. Found: 625.3256.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 1-benzylpiperazine (0.18 mL, 1.0 mmol),1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (30 mL) as described in Preparation 193 gave 0.3 g(40%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 737.6 (M+); Anal. Calc'd for C₄₁H₅₁N₇O₆: C, 66.74; H,6.97; N, 13.29. Found: C, 66.67; H, 7.08; N, 13.09.

Example 113

Reaction of the product of Preparation 221 (0.28 g, 0.38 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.19 g (70%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 637 (M+); Anal. Calc'd forC₃₆H₄₃N₇O₄.3.5HCl: C, 56.49; H, 6.12; N, 12.81. Found: C, 56.77; H,6.44; N, 12.31.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 1-((3-trifluoromethyl)-2-pyridyl)piperazine (0.23 g, 1.0mmol), 1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (40 mL) as described in Preparation 193 gave 0.5 g(63%) of the product as a tan foam: ¹H-NMR is consistent with structure;MS (ion spray) 793 (M+1).

Example 114

Reaction of the product of Preparation 222 (0.42 g, 0.53 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.34 g (85%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (ion spray) 693 (M+1); Anal.Calc'd for C₃₅H₃₉N₆O₄F₃.2.3HCl: C, 54.13; H, 5.36; N, 14.43. Found: C,54.00; H, 5.55; N, 14.07.

To a solution of d-pipecolinic acid, 2.0 g (15.5 mmol) in 30 mL of 4Nsodium hydroxide as 0° C. was added 2.9 mL of benzyl chloroformatedropwise. The mixture was stirred overnight slowly warming to ambienttemperature then was quenched into 5N hydrochloric acid. The mixture wasextracted with chloroform. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated toyield 4.1 g (100%) of the desired product as a colorless oil: ¹H-NMR isconsistent with structure; MS (FD) 264 (M+).

A solution of the product of Preparation 223, 4.1 g (15.5 mmol) andp-toluenesulfonic acid, 0.6 g in 100 mL of absolute ethanol was refluxedfor 7 h. The mixture was quenched with solid sodium bicarbonate andconcentrated. The residue was partitioned between ethyl acetate andwater and extracted with ethyl acetate. The combined organic extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was chromatographed on silica gel usingchloroform as eluant to yield 0.91 g (20%) of the desired product as acolorless oil: ¹H-NMR is consistent with structure; MS (FD) 291 (M+);Anal. Calc'd for C₁₆H₂₁NO₄: C, 65.96; H, 7.27; N, 4.81. Found: C, 66.21;H, 7.23; N, 4.93.

A solution of the product of Preparation 224, 0.9 g (3.0 mmol) in 20 mLof ethyl acetate and 40 mL of absolute ethanol was added to a slurry of10% palladium on carbon, 0.5 g in 20 mL of ethyl acetate. The slurry washydrogenated at 40 psi for 40 min, then was filtered through celite andconcentrated to yield 0.3 g (64%) of the desired product as a colorlessoil: This material was carried on without purification.

Reaction of the product of Preparation 8 from Examples Part 1 (1.1 g,1.9 mmol), the product of Preparation 225 (0.3 g, 1.9 mmol),1-hydroxybenzotriazole (0.28 g, 2.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 0.43 g, 2.1 mmol),dimethylformamide (40 mL), as described in Preparation 193 gave 0.81 g(59%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 719 (M+); Anal. Calc'd for C₃₈H₅₀N₆O₈: C, 63.49; H,7.01; N, 11.69. Found: C, 62.98; H, 7.33; N, 11.51.

Example 115

Reaction of the product of Preparation 226 (0.75 g, 1.0 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.6 g (87%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 619 (M+); Anal. Calc'd forC₃₃H₄₂N₆O₆.2HCl: C, 57.31; H, 6.41; N, 12.15. Found: C, 57.09; H, 6.50;N, 12.04.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), ethyl nipecotate (0.27 mL, 1.7 mmol), 1-hydroxybenzotriazole(0.25 g, 1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4g, 1.9 mmol), dimethylformamide (80 mL) as described in Preparation 193gave 0.97 g (79%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 718 (M+).

Example 116

Reaction of the product of Preparation 227 (0.91 g, 1.26 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.7 g (84%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 618 (M+); Anal. Calc'd forC₃₃H₄₂N₆O₆.2.2HCl: C, 56.71; H, 6.37; N, 12.02. Found: C, 56.71; H,6.44; N, 12.45.

Reaction of the product of Preparation 8 from Examples Part 1 (0.7 g,1.2 mmol), 3,5-dimethylpiperidine (0.16 mL, 1.2 mmol),1-hydroxybenzotriazole (0.18 g, 1.32 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.32 mmol),dimethylformamide (80 mL) as described in Preparation 193 gave 0.8 g(100%) of the desired product as a tan solid: ¹H-NMR is consistent withstructure; MS (FD) (674 (M+).

Example 117

Reaction of the product of Preparation 228 (0.47 g, 0.7 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as in Example 86gave 0.4 g (93%) of the desired product as a yellow solid: ¹H-NMR isconsistent with structure; MS (high res) calc'd for C32H43N6O4:575.3346. Found: 575.3341.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 4-phenylpiperidine (0.28 g, 1.7 mmol), 1-hydroxybenzotriazole(0.26 g, 1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4g, 1.9 mmol), dimethylformamide (80 mL) as described in Preparation 193gave 0.92 g (75%) of the desired compound as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 722 (M+).

Example 118

Reaction of the product of Preparation 229 (0.88 g, 1.2 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.77 g (96%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 622.2 (M+); Anal. Calc'dfor C₃₆H₄₂N₆O₄.2.3HCl: C, 61.19; H, 6.33; N, 11.89. Found: C, 61.02; H,6.35; N, 11.97.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-(3-trifluoromethylphenyl)piperidine hydrochloride (DE3500898, DE 2048589) (0.27 g, 1.0 mmol), triethylamine (0.16 mL, 1.1mmol), 1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (40 mL) as described in Preparation 193 gave 0.4 g(50%) of the desired product as a tan foam: ¹H-NMR is consistent with

structure; MS (FD) 791 (M+); Anal. Calc'd for C₄₂H₄₉F₃N₆O₆: C, 63.79; H,6.35; N, 10.63. Found: C, 63.56; H, 6.53; N, 10.57.

Example 119

Reaction of the product of Preparation 229A (0.36 g, 0.45 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.34 g (100%) of the desired product. ¹H-NMR isconsistent with structure; MS (FD) 690 (M+); Anal. Calc'd forC₃₇H₄₁N₆O₄F₃.2.5HCl: C, 56.86; H, 5.61; N, 10.75. Found: C, 56.72; H,5.88; N, 10.48.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-(4-methoxyphenyl)piperidine hydrochloride (WO 9518118, EP630887) (0.27 g, 1.0 mmol), triethylamine (0.16 mL, 1.1 mmol),1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (40 mL), as described in Preparation 193 gave 0.45 g(60%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 754 (M+); Anal. Calc'd for C₄₂H₅₂N₆O₇: C, 67.00; H,6.96; N, 11.16. Found: C, 66.66; H, 7.40; N, 10.95.

Example 120

Reaction of the product of Preparation 230 (0.4 g, 0.53 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86 gave 0.32 g (84%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 652 (M+); Anal. Calc'd forC₃₇H₄₄N₆O₅.2HCl: C, 61.24; H, 6.39; N, 11.58. Found: C, 60.97; H, 6.38;N, 11.33.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-(2-methoxyphenyl)piperidine (0.19 g, 1.0 mmol),1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (30 mL) as described in Preparation 193 gave 0.63 g(84%) of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (FD) 752 (M+); Anal. Calc'd for C₄₂H₅₂N₆O₇.0.1H2O: C,65.44; H, 7.06; N, 10.90. Found: C, 65.56; H, 7.13; N, 10.89.

Example 121

Reaction of the product of Preparation 231 (0.59 g, 0.78 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.42 g (74%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 652 (M+); Anal. Calc'd forC₃₇H₄₄N₆O₅.2HCl: C, 61.24; H, 6.39; N, 11.58. Found: C, 60.94; H, 6.35;N, 11.33.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), ethyl isonipecotate (0.27 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (60 mL) as described in Preparation 193 gave 0.87 g(71%) of the desired product as a yellow foam: ¹H-NMR is consistent withstructure; MS (FD) 718 (M+).

Example 122

Reaction of the product of Preparation 232 (0.85 g, 1.2 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as in Example 86gave 0.72 g (91%) of the desired product as a white solid: ¹H-NMR isconsistent with structure; MS (FD) 618 (M+); Anal. Calc'd forC₃₃H₄₂N₆O₆.2.6HCl: C, 55.56; H, 6.30; N, 11.78. Found: C, 55.89; H,6.34; N, 12.27.

Reaction of the product of Preparation 8 from Examples Part 1 (0.84 g,1.45 mmol), 4-methoxypiperidine hydrochloride (Baker, et al.; J. Med.Chem. 1992, 35(10), 1722-34) (0.22 g, 1.45 mmol), triethylamine (0.22mL, 1.45 mmol), 1-hydroxybenzotriazole (0.21 g, 1.6 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.32 g, 1.6 mmol),dimethylformamide (40 mL) as described in Preparation 193 gave 0.74 g(76%) of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (FD) 676.6 (M+); Anal. Calc'd for C₃₆H₄₈N₆O₇: C, 63.89; H,7.15; N, 12.42. Found: C, 63.84; H, 7.17; N, 12.12.

Example 123

Reaction of the product of Preparation 233 (0.66 g, 1.0 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL) as described inExample 86 gave 0.54 g (84%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 576.3 (M+); Anal. Calc'dfor C₃₁H₄₀N₆O₅.2.5HCl: C, 55.75; H, 6.41; N, 12.58. Found: C, 55.86; H,6.52; N, 12.27.

A slurry of 4-ethylpyridine, 10 g (93.3 mmol) and 5% Rh/C, 5 g in 135 mLof absolute ethanol was hydrogenated at 60 psi and 50° C. overnight. Thereaction mixture was filtered through celite and distilled atatmospheric pressure to yield 3.6 g (34%) of the desired product as acolorless oil: ¹H-NMR is consistent with structure; MS (FD) 114 (M+);b.p.=153-155° C.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-ethylpiperidine (0.13 g, 1.0 mmol), 1-hydroxybenzotriazole(0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23g, 1.1 mmol), dimethylformamide (40 mL) as described in Preparation 193gave 0.57 g (85%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (ion spray) 675.4 (M+1). Anal. Calc'd forC₃₇H₅₀N₆O₆.0.1CHCl₃: C, 64.88; H, 7.35; N, 12.24. Found: C, 65.01; H,6.95; N, 12.16.

Example 124

Reaction of the product of Preparation 235 (0.57 g, 0.84 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.34 g (63%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (ion spray) 575 (M+1); Anal.Calc'd for C₃₂H₄₂N₆O₄.2HCl: C, 59.35; H, 6.85; N, 12.98. Found: C,59.19; H, 6.65; N, 12.80.

A slurry of 4-isopropylpyridine, 15.8 g (130 mmol) and 5% Rh/C, 16 g in125 mL of absolute ethanol was hydrogenated at 60 psi and 50° C. for 18h. The reaction mixture was filtered through celite and distilled atatmospheric pressure to yield 2.4 g (14.4%) of the desired product as acolorless oil: ¹H-NMR is consistent with structure; MS (FD) 127 (M+) ;b.p.=178-180° C.; Anal. Calc'd for C₈H₁₇N: C, 75.52; H, 13.47; N, 11.01.Found: C, 75.36; H, 13.40; N, 11.09.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-isopropylpiperidine (0.13 g, 1.0 mmol),1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (20 mL) as described in Preparation 193 gave 0.55 g(80%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (ion spray) 689.5 (M+1). Anal. Calc'd for C₃₈H₅₀N₆O₆.2HCl:C, 66.26; H, 7.61; N, 12.20. Found: C, 66.16; H, 7.46; N, 12.03.

Example 125

Reaction of the product of Preparation 237 (0.45 g, 0.65 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86 gave 0.37 g (86%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (high res) calc'd forC₃₃H₄₃N₆O₄: 589.3502. Found: 589.3509.

Preparation 238

A slurry of 4-t-butylpyridine, 17.4 g (128 mmol) and 5% Rh/Al₂O₃, 6.8 gin 130 mL of absolute ethanol was hydrogenated at 60 psi and 50° C.overnight. The reaction mixture was filtered through celite anddistilled at atmospheric pressure to yield 7.0 g (39%) of the desiredproduct as a colorless oil: ¹H-NMR is consistent with structure; MS (FD)142 (M+); b.p.=155° C.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-t-butylpiperidine (0.14 g, 1.0 mmol),1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (20 mL) as described in Preparation 193 gave 0.59 g(84%) of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (ion spray) 703.6 (M+1). Anal. Calc'd forC₃₉H₅₂N₆O₆.0.5H₂O: C, 65.80; H, 7.79; N, 11.80. Found: C, 65.63; H,7.55; N, 11.88.

Example 126

Reaction of the product of Preparation 239 (0.48 g, 0.68 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL) as described inExample 86 gave 0.33 g (72%) of the desired product as a white foam:¹H-NMR is consistent with structure; MS (ion spray) 603.4 (M+1); Anal.Calc'd for C₃₄H₄₆N₆O₄.2.2HCl: C, 59.80; H, 7.11; N, 12.30. Found: C,59.63; H, 7.03; N, 12.37.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 4-propylpiperidine (0.22 g, 1.7 mmol), 1-hydroxybenzotriazole(0.26 g, 1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4g, 1.9 mmol), dimethylformamide (60 mL) as described in Preparation 193gave 0.93 g (80%) of the desired product as a yellow foam: ¹H-NMR isconsistent with structure; MS (FD) 688.5 (M+); Anal. Calc'd forC₃₈H₅₂N₆O₆: C, 66.20; H, 7.61; N, 12.20. Found: C, 66.19; H, 7.64; N,12.47.

Example 127

Reaction of the product of Preparation 240 (0.93 g, 1.4 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.8 g (92%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 588.2 (M+); Anal. Calc'dfor C₃₃H₄₃N₆O₄.2.2HCl: C, 59.58; H, 6.98; N, 12.63. Found: C, 59.26; H,7.19; N, 12.82.

To a solution of 4-hydroxypiperidine, 5.0 g (50 mmol) in 80 mL of 4Nsodium hydroxide at 0° C. was added 9.3 mL (65 mmol) of benzylchloroformate dropwise. The reaction mixture was stirred overnight whileslowly warming to ambient temperature, then was poured into 100 mL of 5Nhydrochloric acid. The mixture was extracted with chloroform. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was chromatographed onsilica gel using a gradient of chloroform to 5% methanol/chloroform aseluant to yield 11.5 g (97%) of the desired product as a colorless oil:¹H-NMR is consistent with structure; MS (FD) 235 (M+); Anal. Calc'd forC₁₃H₁₇NO₃: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.39; H, 7.19; N,5.95.

To a solution of the product of Preparation 241, 10.6 g (45 mmol) in 100mL of ether and 100 mL of dimethylformamide at 0° C. was added 2.16 g(54 mmol) of sodium hydride. After stirring for 15 min at 0° C., 4.1 mL(54 mmol) of chloromethyl methyl ether was added dropwise. The reactionmixture was stirred overnight while slowly warming to ambienttemperature and was then concentrated. The residue was partitionedbetween ethyl acetate and water and was extracted with ethyl acetate.The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was chromatographed onsilica gel using 3-5% methanol/chloroform as eluant to yield 6.64 g(65%) of the desired product as a colorless oil: ¹H-NMR is consistentwith structure; MS (FD) 279.1 (M+); Anal. Calc'd for C₁₅H₂₁NO₄: C,64.50; H, 7.58; N, 5.01. Found: C, 65.00; H, 7.20; N, 5.30.

A solution of the product of Preparation 242, 2.0 g (7.1 mmol) in 20 mLof ethyl acetate and 40 mL of absolute ethanol was added to a slurry of10% palladium on carbon, 1.0 g in 20 mL of ethyl acetate. The mixturewas hydrogenated at 40 psi for 4 h then filtered through celite andconcentrated to yield 0.71 g (68%) of the desired product as a colorlessoil: ¹H-NMR is consistent with structure and was carried on withoutfurther characterization.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), the product of Preparation 243 (0.25 g, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.1 mmol),dimethylformamide (30 mL), as described in Preparation 193, gave 0.63 g(53%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 706.5 (M+); Anal. Calc'd for C₃₇H₅₀N₆O₈.0.5H₂O: C,62.08; H, 7.18; N, 11.74. Found: C, 62.12; H, 7.32; N, 11.56.

Example 128

To a solution of the product of Preparation 244, 0.53 g (0.75 mmol) 12mL of dichloromethane was added 6 mL of trifluoroacetic acid. Thereaction mixture was stirred for 2 h, then concentrated. The residue wasslurried in ether and filtered to yield 0.5 g (85%) of the desiredproduct as a white solid: ¹H-NMR is consistent with structure; MS (FD)561.9 (M+); Anal. Calc'd for C₃₀H₃₈N₆O₅.2 trifluoroacetic acid: C,51.65; H, 5.10; N, 10.63. Found: C, 51.88; H, 5.36; N, 10.61.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g ,1.0 mmol), 4-phenoxypiperidine hydrochloride(Boswell, et al.; J. Med.Chem. 1974, 17(9), 1000-8) (0.2 g, 1.0 mmol), triethylamine (0.16 mL,1.1 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (40 mL) as described in Preparation 193, gave 0.55 g(74%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 738 (M+); Anal. Calc'd for C₄₁H₅₀N₆O₇: C, 66.65; H,6.82; N, 11.37. Found: C, 66.35; H, 6.64; N, 11.28.

Example 129

Reaction of the product of Preparation 245 (0.46 g, 0.6 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86, gave 0.3 g (70%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 638.3 (M+); Anal. Calc'dfor C₃₆H₄₂N₆O₅.2HCl: C, 60.76; H, 6.23; N, 11.81. Found: C, 60.62; H,6.32; N, 11.63.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 4-benzylpiperidine (0.3 mL, 1.7 mmol), 1-hydroxybenzotriazole(0.26 g, 1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4g, 1.9 mmol), dimethylformamide (80 mL), as described in Preparation193, gave 0.82 g (66%) of the desired product as a yellow foam: ¹H-NMRis consistent with structure; MS (FD) 736.3 (M+); Anal. Calc'd forC₄₂H₅₂N₆O₆.1.1H₂O: C, 66.66; H, 7.22; N, 11.11. Found: C, 66.47; H,6.92; N, 11.67.

Example 130

Reaction of the product of Preparation 246 (0.8 g, 1.1 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.65 g (88%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 637 (M+); Anal. Calc'd forC₃₇H₄₄N₆O₄.2.1HCl: C, 62.30; H, 6.51; N, 11.78. Found: C, 62.21; H,6.59; N, 12.12.

(0.7 g, 1.2 mmol), 4-benzoylpiperidine hydrochloride (0.27 g, 1.2 mmol),triethylamine (0.18 mL, 1.32 mmol), 1-hydroxybenzotriazole (0.18 g, 1.32mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.32mmol), dimethylformamide (30 mL), as described in Preparation 193 gave0.65 g (72%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 751 (M+).

Example 131

Reaction of the product of Preparation 247 (0.51 g, 0.68 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.47 g (96%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 651 (M+); Anal. Calc'd forC₃₇H₄₂N₆O₅.2HCl: C, 60.49; H, 6.08; N, 11.44. Found: C, 60.44; H, 6.00;N, 11.41.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 4-(4-fluorobenzoyl)piperidine hydrochloride (0.42 g, 1.7mmol), triethylamine (0.26 mL, 1.9 mmol), 1-hydroxybenzotriazole (0.26g, 1.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9mmol), dimethylformamide (80 mL), as described in Preparation 193, gave0.97 g (75%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 768.9 (M+).

Example 132

Reaction of the product of Preparation 248 (0.92 g, 1.2 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.75 g (88%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 669 (M+); Anal. Calc'd forC₃₇H₄₂FN₆O₅.2.7HCl: C,. 57.93; H, 5.74; N, 10.95. Found: C, 57.83; H,5.81; N, 11.20.

Reaction of the product of Preparation 8 from Examples Part 1 (0.7 g,1.2 mmol), 4-(4-chlorobenzoyl)piperidine hydrochloride (0.32 g, 1.2mmol), triethylamine (0.18 mL, 1.32 mmol), 1-hydroxybenzotriazole (0.18g, 1.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g,1.32 mmol), dimethylformamide (30 mL), as described in Preparation 193,gave 0.83 g (89%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 785 (M+).

Example 133

Reaction of the product of Preparation 249 (0.64 g, 0.82 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.51 g (82%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 685 (M+); Anal. Calc'd forC₃₇H₄₁N₆O₅Cl.2HCl: C, 58.61; H, 5.72; N, 11.08. Found: C, 58.34; H,5.93; N, 11.00.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-(4-methylbenzoyl)piperidine hydrochloride (0.24 g, 1.0mmol), triethylamine (0.16 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.15g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol), dimethylformamide (30 mL), as described in Preparation 193, gave0.54 g (71%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 765.4 (M+); Anal. Calc'd for C₄₃H₅₂N₆O₇: C,67.52; H, 6.85; N, 10.99. Found: C, 67.32; H, 6.65; N, 10.76.

Example 134

Reaction of the product of Preparation 250 (0.5 g, 0.65 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86, gave 0.33 g (69%) of the desired product as a white solid:¹H-NMR is consistent with structure; (FD) 655.2 (M+); Anal. Calc'd forC₃₈H₄₄N₆O₅Cl.2.3HCl: C, 60.96; H, 6.23; N, 11.23. Found: C, 60.92; H,6.55; N, 11.10.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-(4-methoxybenzoyl)piperidine hydrochloride (0.26 g, 1.0mmol), triethylamine (0.16 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.15g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol), dimethylformamide (40 mL), as described in Preparation 193, gave0.23 g (29%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 780.8 (M+); Anal. Calc'd for C₄₃H₅₂N₆O₈: C,66.14; H, 6.71; N, 10.76. Found: C, 66.14; H, 6.60; N, 10.65.

Example 135

Reaction of the product of Preparation 251 (0.2 g, 0.26 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86, gave 0.19 g (100%) of the desired product. ¹H-NMR isconsistent with structure; MS (FD) 681.3 (M+); Anal. Calc'd forC₃₈H₄₄N₆O₆.2HCl: C, 60.56; H, 6.15; N, 11.15. Found: C, 60.43; H, 6.29;N, 10.89.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-(alpha-cyanobenzyl)piperidine hydrochloride (0.24 g, 1.0mmol), triethylamine (0.16 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.15g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1mmol), dimethylformamide (40 mL), as described in Preparation 193, gave0.4 g (53%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 761.7 (M+); Anal. Calc'd for C₄₃H₅₁N₇O₆: C,67.79; H, 6.75; N, 12.87. Found: C, 67.54; H, 6.45; N, 12.67.

Example 136

Reaction of the product of Preparation 252 (0.31 g, 0.4 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86, gave 0.22 g (76%) of the desired product as a tan foam:¹H-NMR is consistent with structure; MS (FD) 661.1 (M+); Anal. Calc'dfor C₃₈H₄₃N₇O₄.2HCl: C, 62.12; H, 6.17; N, 13.35. Found: C, 61.95; H,8.38; H, 13.19.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-(2-ethyl-2-naphthyl))piperidine hydrochloride (Efange etal., J. Med Chem. 1993 36(9), 1278-83) (0.28 g, 1.0 mmol), triethylamine(0.16 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (40 mL), as described in Preparation 193, gave 0.58 g(74%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 801 (M+); Anal. Calc'd for C₄₇H₅₆N₆O₆: C, 70.48; H,7.05; N, 10.49. Found: C, 70.52; H, 6.87; N, 10.50.

Example 137

Reaction of the product of Preparation 253 (0.5 g, 0.62 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86, gave 0.22 g (46%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 701 (M+).

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-(phenpropyl)piperidine (0.2 g, 1.0 mmol), triethylamine(0.16 mL, 1.1 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (40 mL), as described in Preparation 193, gave 0.58 g(76%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 765.4 (M+); Anal. Calc'd for C₄₄H₅₆N₆O₆: C, 69.09; H,7.38; N, 10.99. Found: C, 68.95; H, 7.29; N, 11.04.

Example 138

Reaction of the product of Preparation 254 (0.41 g, 0.5 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86, gave 0.32 g (87%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD)664 (M+); Anal. Calc'd forC₃₉H₄₈N₆O₄.2HCl: C, 63.49; H, 6.83; N, 11.39. Found: C, 63.30; H, 6.77;N, 11.29.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 4,4-dimethylpiperidine hydrochloride (0.26 g, 1.7 mmol),triethylamine (0.26 mL, 1.9 mmol), 1-hydroxybenzotriazole (0.26 g, 1.9mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL), as described in Preparation 193, gave 0.84 g(73%) of the desired product as a tan solid: ¹H-NMR is consistent withstructure; MS (FD) 674 (M+).

Example 139

Reaction of the product of Preparation 255 (0.82 g, 1.2 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.65 g (89%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 574.2 (M+).

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 3-azaspiro(5.5)undecane hydrochloride (Knoelker, et al;Synlett. 1992, Issue 5, 371-87)(0.19 g, 1.0 mmol), triethylamine (0.16mL, 1.1 mmol), 1-hydroxybenzotriazole (0.15 g, 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.1 mmol),dimethylformamide (40 mL), as described in Preparation 193, gave 0.42 g(60%) of the desired compound as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 715 (M+); Anal. Calc'd for C₄₀H₅₄N₆O₆: C, 67.21; H,7.61; N, 11.76. Found: C, 67.13; H, 7.38; N, 11.71.

Example 140

Reaction of the product of Preparation 257 (0.37 g, 0.5 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86, gave 0.32 g (94%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 614 (M+); Anal. Calc'd forC₃₅H₄₆N₆O₄.2.3HCl: C, 60.17; H, 6.97; N, 12.03. Found: C, 60.14; H,7.13; N, 11.82.

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), 4-(10,11-dihydro-5H-dibenzo(A,D)cyclohepten-5-yl)piperidine(U.S. Pat. No. 4,626,542) (0.28 g, 1.0 mmol), 1-hydroxybenzotriazole(0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23g, 1.1 mmol), dimethylformamide (40 mL), as described in Preparation193, gave 0.69 g (82%) of the desired compound as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 839 (M+).

Example 141

Reaction of the product of Preparation 258 (0.63 g, 0.75 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86, gave 0.44 g (72%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 739 (M+); Anal. Calc'd forC₄₅H₅₀N₆O₄.2HCl: C, 66.58; H, 6.46; N, 10.35. Found: C, 66.41; H, 6.62;N, 10.25.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.0 mmol), 4-cyano,4-phenylpiperidine hydrochloride (0.38 g, 1.7 mmol),triethylamine (0.26 mL, 1.9 mmol), 1-hydroxybenzotriazole (0.26 g, 1.9mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (40 mL), as described in Preparation 193, gave 1.0 g(79%) of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (FD) 747.8 (M+).

Example 142

Reaction of the product of Preparation 259 (1.0 g, 1.3 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.71 g (76%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 647.2 (M+); Anal. Calc'dfor C₃₇H₄₁N₇O₄.2.6HCl: C, 59.85; H, 5.92; N, 13.20. Found: C, 59.76; H,5.88; N, 13.10.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.0 mmol), 4-acetyl-4-phenylpiperidine hydrochloride (0.4 g, 1.7 mmol),triethylamine (0.26 mL, 1.9 mmol), 1-hydroxybenzotriazole (0.26 g, 1.9mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL), as described in Preparation 193, gave 0.52 g(40%) of the desired product as a white foam: H-NMR is consistent withstructure; MS (FD) 765 (M+); Anal. Calc'd for C₄₃H₅₂N₆O₇.0.1H₂O: C,65.97; H, 6.95; N, 10.73. Found: C, 65.68; H, 6.93; N, 11.17.

Example 143

Reaction of the product of Preparation 260 (0.5 g, 0.65 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.44 g (96%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 664.4 (M+); Anal. Calc'dfor C₃₈H₄₃N₆O₅.2.7HCl: C, 59.80; H, 6.17; N, 11.01. Found: C, 59.61; H,6.18; N. 11.24.

Reaction of the product of Preparation 8 from Examples Part 1 (0.7 g,1.2 mmol), 4-phenyl-4-propionylpiperidine hdyrochloride (0.3 g, 1.2mmol), triethylamine (0.18 mL, 1.32 mmol), 1-hydroxybenzotriazole (0.18g, 1.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g,1.32 mmol), dimethylformamide (40 mL), as described in Preparation 193,gave 0.71 g (76%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 779 (M+); Anal. Calc'd forC₄₄H₅₄N₆O₇: C, 67.85; H, 6.99; N, 10.79. Found: C, 67.56; H, 7.10; N,10.95.

Example 144

Reaction of the product of Preparation 261 (0.58 g, 0.74 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.54 g (100%) of the desired product. ¹H-NMR isconsistent with structure; MS (FD) 678 (M+); Anal. Calc'd forC₃₉H₄₆N₆O₅.2.6HCl: C, 60.55; H, 6.33; N, 10.86. Found: C, 60.40; H,6.27; N, 10.79.

Reaction of the product of Preparation 8 from Examples Part 1 (0.7 g,1.2 mmol), 4-butyryl-4-phenylpiperidine hdyrochloride (0.3 g, 1.2 mmol),triethylamine (0.18 mL, 1.32 mmol), 1-hydroxybenzotriazole (0.18 g, 1.32mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.32mmol), dimethylformamide (40 mL), as described in Preparation 193, gave0.76 g (80%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 793 (M+).

Example 145

Reaction of the product of Preparation 262 (0.65 g, 0.82 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.5 g (80%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 692 (M+); Anal. Calc'd forC₄₀H₄₈N₆O₅.2.3HCl: C, 61.86; H, 6.53; N, 10.82. Found: C, 61.96; H,6.63; N, 10.60.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 1,2,3,6-tetrahydropyridine (0.16 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL), as described in Preparation 193, gave 0.63 g(57%) of the desired product as a tan solid: ¹H-NMR is consistent withstructure; MS (FD) 644 (M+); Anal. Calc'd for C₃₅H₄₄H₆O₆: C, 65.20; H,6.88; N, 13.03. Found: C, 65.30; H, 7.04; N, 13.14.

Example 146

Reaction of the product of Preparation 263 (0.62 g, 0.96 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.53 g (95%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (high res) calc'd forC₅₀H₃₇N₆O₄: 545.2876. Found: 545.2883.

Reaction of the product of Preparation 8 from Examples Part 1 (0.7 g,1.2 mmol), 4-phenyl-1,2,3,6-tetrahydropyridine (0.16 g, 1.2 mmol),1-hydroxybenzotriazole (0.18 g, 1.32 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.27 g, 1.32 mmol),dimethylformamide (40 mL), as described in Preparation 193, gave 0.36 g(50%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (FD) 721.2 (M+); Anal. Calc'd for C₄₁H₄₈N₆O₆.0.5H₂O: C,67.47; H, 6.77; N, 11.51. Found: C, 67.56; 6.81; N, 11.20.

Example 147

Reaction of the product of Preparation 264 (0.34 g, 0.47 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 86, gave 0.28 g (85%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (ion spray) 621.4 (M+1).

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 3,5-dimethylpiperidine (0.23 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL), as described in Preparation 193, gave 0.93 g(81%) of the desired product as a tan solid: ¹H-NMR is consistent withstructure; MS (FD) 674 (M+).

Example 148

Reaction of the product of Preparation 265 (0.78 g, 1.16 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.63 g (89%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 574 (M+); Anal. Calc'd forC₃₂H₄₁N₆O₄.2.8HCl: C, 56.79; H, 6.67; N, 12.42. Found: C, 56.75; H,6.70; N, 12.12.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), decahydroquinoline (0.26 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (80 mL), as described in Preparation 193, gave 1.0 g(83%) of the desired product as a tan solid: ¹H-NMR is consistent withstructure; MS (FD) 700.5 (M+); Anal. Calc'd for C₃₉H₅₂N₆O₆: C, 66.84; H,7.48; N, 11.99. Found: C, 66.69; H, 7.48; N, 12.15.

Example 149

Reaction of the product of Preparation 266 (0.93 g, 1.3 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.77 g (93%) of the desired product as a yellow solid:¹H-NMR is consistent with structure; MS (FD) 600 (M+); Anal. Calc'd forC₃₄H₄₃N₆O₄.2.6HCl: C, 58.71; H, 6.75; N, 12.08. Found: C, 58.54; H,6.98; N, 11.93.

Reaction of the product of Preparation 8 from Examples Part 1 (1.0 g,1.7 mmol), 1,2,3,4-tetrahydroisoquinoline (0.22 mL, 1.7 mmol),1-hydroxybenzotriazole (0.26 g, 1.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 1.9 mmol),dimethylformamide (40 mL), as described in Preparation 193, gave 0.91 g(77%) of the desired product as a white foam: ¹H-NMR is consistent withstructure; MS (FD) 694.8 (M+)

Example 150

Reaction of the product of Preparation 267 (0.88 g, 1.3 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 86, gave 0.87 g (100%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 594.3 (M+); Anal. Calc'dfor C₃₄H₃₈N₆O₄.2.5HCl: C, 59.54; H, 5.95; N, 12.25. Found: C, 59.31; H,6.02; N, 12.06.

To a solution of tert-butylcarbonyl-alpha-aminoisobutic acid(10.0 g, 50mmol) and methyl iodide, 3.6 mL (55 mmol) in 200 mL of tetrahydrofuranstirring at 0° C. was added 4.4 g (55 mmol) of sodium hydride. After 1h, the mixture was warmed to ambient temperature and stirred overnight.The reaction mixture was quenched with water, concentrated, anddissolved in water. The aqueous solution was acidified to pH=3.4 withsolid citric acid. Ethyl acetate was added and the mixture was extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried over sodium sulfate, filtered and concentrated to yield10.8 g (100%) of the desired product as a white solid: ¹H-NMR isconsistent with structure; MS (ion spray) 218 (M+1).

To a solution of the product of Preparation 268, 9.75 g (45.0 mmol),tert-butyloxycarbonyl-O-benzyl-D-serin, 11.0 g (45.0 mmol), Hunig'sbase, 28 mL (157.5 mmol) and 1-hydroxybenzotriazole, 6.8 g (49.5 mmol)in 100 mL of dimethylformamide at 0° C., was added 9.5 g (49.5 mmol) of1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride. Thereaction mixture was slowly warmed to ambient temperature, stirredovernight, then concentrated. The residue was partitioned between ethylacetate and water and extracted with ethyl acetate. The combined organicextracts were washed with 0.1 N hydrochloric acid, saturated sodiumbicarbonate and brine, dried over sodium sulfate, filtered andconcentrated. The residue was chromatographed on silica gel using 3%methanol/chloroform as eluant to yield 13.8 g (75%) of the desiredproduct as a tan oil: ¹H-NMR is consistent with structure; MS (ionspray) 409.4 (M+1); Anal. Calc'd for C₂₁H₃₂N₂O₆: C, 61.60; H, 8.12; N,6.84. Found: C, 61.45; H, 8.10; N, 6.87.

To a solution of the product of Preparation 269, 0.5 g (1.22 mmol) in 10mL of tetrahydrofuran was added a solution of lithium hydroxide, 0.09 g(3.7 mmol) in 5 mL of water. The reaction mixture was stirred for 2 hand acidified to pH=2.4 with 1N hydrochloric acid. Water was added andthe mixture was extracted with ethyl acetate. The combined organicextracts were washed with brine, dried over sodium sulfate, filtered,and concentrated to yield 0.48 g (100%) of the desired product as aclear oil: ¹H-NMR is consistent with structure; MS (ion spray) 395.2(M+1); Anal. Calc'd for C₂₀H₃₀N₂O₆: C, 60.90; H, 7.67; N, 7.10. Found:C, 61.04; H, 7.70; N, 7.34.

Reaction of the product of Preparation 165 (4.5 g, 14.7 mmol), 10%palladium on carbon (5.8 g), tetrahydrofuran (120 mL), the product ofPreparation 270 (5.8 g, 14.7 mmol), 1-hydroxybenzotriazole (2.2 g, 16.2mmol), dicyclohexylcarbodiimide (3.3 g, 16.2 mmol), as in Example 63,gave 6.55 g (68%) of the desired compound as a tan foam: ¹H-NMR isconsistent with structure; MS (ion spray) 652.4 (M+1).

Reaction of the product of Preparation 271 (6.5 g, 10.0 mmol), lithiumhydroxide (0.3 g, 12.0 mmol), dioxane (100 mL), water (50 mL), as inExample 63, gave 6.24 g (100%) of the desired compound as a tan foam:¹H-NMR is consistent with structure; MS (ion spray) 624.4 (M+1); Anal.Calc'd for C₄₃H₄₁N₅O₈: C, 61.62; H, 6.63; N, 11.23. Found: C, 61.34; H,6.68; N, 11.33.

Reaction of the product of Preparation 272 (6.1 g, 1.0 mmol),4-methylpiperidine (1.2 mL, 1.0 mmol), 1-hydroxybenzotriazole (1.5 g,1.1 mmol), dicyclohexylcarbodiimide (2.3 g, 1.1 mmol), dimethylformamide(90 mL), as in Example 63, gave 6.18 g (88%) of the desired product as atan foam: ¹H-NMR is consistent with structure; MS (ion spray) 705.6(M+1); Anal. Calc'd for C₃₈H₅₂N₆O₇: C, 64.75; H, 7.44; N, 11.92. Found:C, 64.63; H, 7.39; N, 11.99.

Examples 151 and 152

Reaction of the product of Preparation 273 (5.65 g, 8.0 mmol),trifluoroacetic acid (16 mL), dichloromethane (40 mL), as in Example 63,gave 4.08 g (85%) of the desired product as the free base: ¹H-NMR isconsistent with structure; MS (ion spray) 605.4 (M+1); Anal. Calc'd forC₃₃H₄₄N₆O₅: C, 65.54; H, 7.33; N, 13.90. Found: C, 65.30; H, 7.54; N,13.93. Resolution of the diastereomers (3.5 g, 5.8 mmol) by chiral HPLCgave the respective isomers which were individually treated with asaturated solution of hydrochloric acid in diethyl ether to give thedesired products:

Example 151. (Isomer 1): 1.4 g (36%); ¹H-NMR is consistent withstructure; t_(R)=6.50 min; MS (ion spray) 605.1 (M+1); Anal. Calc'd forC₃₃H₄₄N₆O₅.2.4HCl: C, 57.26; H, 6.76; N, 12.14. Found: C, 57.30; H,6.67; N, 12.00.

Example 152. (Isomer 2): 1.43 g (36%); ¹H-NMR is consistent withstructure; t_(R)=7.91 min; MS (ion spray) 605.1 (M+1); Anal. Calc'd forC₃₃H₄₄N₆O₅.2.2HCl: C, 57.87; H, 6.80; N, 12.27. Found: C, 57.71; H,6.84; N, 12.09.

To a solution of 5-phenylvaleric acid, 19.55 g (110 mmol) in 100 mL ofabsolute ethanol was added 2.0 g (10.4 mmol) of p-toluenesulfonic acid.The mixture was heated to reflux overnight, cooled to ambienttemperature and concentrated. The residue was chromatographed on silicagel using 20% ethyl acetate/hexanes as eluant to yield 21.3 g (94%) ofthe desired product as a colorless oil: ¹H-NMR is consistent withstructure; MS (FD) 206 (M+); Anal. Calc'd for C₁₂H₁₈O₂: C, 75.69; H,8.81. Found: C, 75.69; H, 8.91.

To a solution of diisopropylamine, 11.5 mL (80 mmL) in 250 mL oftetrahydrofuran at −78° C. was added 50.0 mL of 1.0 M n-butyl lithiumdropwise. After stirring at −78° C. for 20 minutes, 15.0 mL (116 mmol)of trimethylsilyl chloride was added followed by a solution of theproduct of Preparation 274 (15.0 g, 72.5 mmol) in 50 mL oftetrahydrofuran. The reaction mixture was stirred 1 h at −78° C. and wasthen concentrated. To a slurry of the resulting white solid in 500 mL ofethylene glycol dimethylether at −78° C. was added 13.5 g (76.1 mmol) ofN-bromosuccinimide. The reaction mixture was stirred 3 h at −78° C.,then was quenched with water and extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was chromatographed onsilica gel using 2.5% ethyl acetate/hexanes to yield 14.8 g (72%) of thedesired product as a yellow oil: ¹H-NMR is consistent with structure; MS(FD) 284, 286 (M+).

To a slurry of sodium hydride, 2.4 g (60 mmol) in 300 mL ofdimethylformamide at 0° C. was added 6.8 g (60 mmol) of4-nitroimidazole. After stirring for 20 min at 0° C., a solution of 14.1g (50 mmol) of the product of

Preparation 275 in 30 mL of dimethylformamide was added. The reactionmixture was stirred overnight, slowly warming to ambient temperature andwas concentrated. The residue was partitioned between ethyl acetate andwater and was extracted with ethyl acetate. The combined organicextracts were washed with brine, dried over sodium sulfate, filtered andconcentrated. The resulting residue was chromatographed on silica gelusing a chloroform as eluant to yield 12.7 g (71%) of the desiredproduct as an orange oil: ¹H-NMR is consistent with structure; MS (FD)317 (M+); Anal. Calc'd for C₁₆H₁₉N₃O₄: C, 60.56; H, 6.04; N, 13.24.Found: C, 60.78; H, 6.09; N, 12.98.

To a solution of the product of Preparation 276, 12.2 g (38.4 mmol) in60 mL of tetrahydrofuran was added 40 mL of 5N sodium hydroxide. Themixture was stirred at ambient temperature for 1 h, then acidified topH=3 with 5N hydrochloric acid and extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated to yield 9.3 g (84%) of the desiredproduct as an orange oil: ¹H-NMR is consistent with structure; MS (FD)290 (M+).

To a solution of the product of Preparation 277, 9.0 g (31 mmol),pyrrolidine, 2.6 mL (31 mmol) and 1-hydroxybenzotriazole, 4.6 g (34.1mmol) in 200 mL of dimethylformamide was added 7.0 g (34.1 mmol) ofdicyclohexylcarbodiimide. The reaction mixture was stirred overnight atambient temperature and was then concentrated in vacuo. The residue waspartitioned between ethyl acetate and water and was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The residue waschromatographed on silica gel using 5% methanol/chloroform as eluant toyield 10.3 g (97%) of the desired product as a tan oil: ¹H-NMR isconsistent with structure; MS (FD) 312 (M+).

To a slurry of 0.8 g of 10% palladium on carbon in 20 mL of dioxane wasadded a solution of 0.8 g (3.5 mmol) of the product of Preparation 278in 20 mL of dioxane. The mixture was hydrogenated at 40 psi of hydrogenfor 3 h and filtered through celite. To this solution was added 1.2 g(5.8 mmol) of the product of Preparation 1d, 0.52 g (3.85 mmol) of1-hydroxybenzotriazole and 0.8 g (3.85 mmol) ofdicyclohexylcarbodiimide. The reaction was stirred overnight at ambienttemperature, filtered and concentrated. The residue was partitionedbetween ethyl acetate and water and was extracted with ethyl acetate.The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The resulting residue waschromatographed on silica gel using 2.5% methanol/chloroform as eluantto yield 0.65 g (16%) of the desired product as a red foam: ¹H-NMR isconsistent with structure; MS (FD) 674 (M+).

Example 153

To a solution of the product of Preparation 278A, 0.55 g (0.8 mmol) in24 mL of dichloromethane was added 8 mL of a trifluoroacetic acid. Thereaction mixture was stirred for 2 h, quenched with aqueous sodiumcarbonate and extracted with chloroform. The combined organic extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated. To a solution of the residue in ethyl acetate was addedether/hydrochloric acid. The resultant slurry was concentrated to yield0.47 g (94%) of the desired product as a tan solid: ¹H-NMR is consistentwith structure; MS (FD) 573.9 (M+); Anal. Calc'd for C₃₂H₄₂N₆O₄.0.2HCl:C, 59.35; H, 6.85; N, 12.98. Found: C, 59.04; H, 6.96; N, 12.52.

To a solution of hydrocinnamic acid, 12.35 g (82.2 mmol) in 300 mL ofdichloromethane was added 4.2 mL (82.2 mmol) of bromine dropwise. Thereaction mixture was illuminated for 15 min and then stirred anadditional 15 min and concentrated. The residue was trituated withether/hexanes to yield 14.7 g (78%) of the desired product as a whitesolid: ¹H-NMR is consistent with structure; MS (FD) 228, 230 (M+); Anal.Calc'd for C₉H₉O₂Br: C, 47.19; H, 3.96. Found: C, 47.28; H, 4.02.

To a slurry of sodium hydride, 1.1 g (27.3 mmol) in 50 mL ofdimethylformamide at 0° C. was added 3.1 g (27.3 mmol) of4-nitroimidazole. The resulting mixture was stirred 20 min, then 3.0 g(13.0 mmol) of product of Preparation 279 was added. The reactionmixture was stirred overnight slowly warming to ambient temperature,then concentrated. The residue was partitioned between ethyl acetate and1N hydrochloric acid and was basified to pH=3.0 with 1N sodiumhydroxide. The aqueous layer was extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was absorbed onto asilica pad and chromatographed on silica gel using a gradient of 10-40%methanol/chloroform to yield 0.55 g (14.4%) of the desired product as awhite solid: ¹H-NMR is consistent with structure; MS (FD) 261 (M+).

To a solution of the product of Preparation 280, 2.4 g (9.3 mmol),pyrrolidine, 0.77 mL (9.3 mmol) and 1-hydroxybenzotriazole, 1.6 g (10.2mmol) in 200 mL of dimethylformamide was added 2.1 g (10.2 mmol) ofdicyclohexylcarbodiimide. The reaction mixture was stirred overnight atambient temperature and was then concentrated in vacuo. The residue waspartitioned between ethyl acetate and water and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The residue waschromatographed on silica gel using 2.5% methanol/chloroform as eluantto yield 0.84 g (29%) of the desired product as a white foam: ¹H-NMR isconsistent with structure; MS (FD) 314 (M+).

To a slurry of 0.7 g of 10% palladium on carbon in 30 mL of ethylacetate was added a solution of 0.8 g (2.5 mmol) of the product ofPreparation 281 in 30 mL of ethyl acetate, 60 mL of tetrahydrofuran and60 mL of ethanol. The mixture was hydrogenated at 40 psi of hydrogen for1 h, filtered through celite and concentrated. The residue was dissolvedin 60 mL of dimethylformamide. To this solution was added 0.95 g (2.5mmol) of the product of Preparation 1d, 0.37 g (2.75 mmol) of1-hydroxybenzotriazole and 0.57 g (2.75 mmol) ofdicyclohexylcarbodiimide. The reaction was stirred overnight at ambienttemperature, filtered and concentrated. The residue was partitionedbetween ethyl acetate and water and was extracted with ethyl acetate.The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The resulting residue waschromatographed on silica gel using 2.5% methanol/chloroform as eluantto yield 0.32 g (20%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (FD) 646.3 (M+).

Example 154

To a solution of the product of Preparation 282, 0.25 g (0.38 mmol) in12 mL of dichloromethane was added 4 mL of trifluoroacetic acid. Thereaction mixture was stirred for 2 h, quenched with aqueous sodiumcarbonate and extracted with chloroform. The combined organic extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated. To a solution of the residue in 20 mL of ethyl acetate wasadded 40 mL of ether.hydrochloric acid. The resultant slurry wasconcentrated to yield 0.22 g (96%) of the desired product as a tansolid: ¹H-NMR is consistent with structure; MS (high res) calc'd forC₃₀H₃₉N₆O₄: 547.3033. Found: 547.3037.

To a slurry of sodium hydride, 6.72 g (168 mmol) in 400 mL ofdimethylformamide at 0° C. was added 19.0 g (168 mmol) of4-nitroimidazole. The resulting slurry was stirred 20 min, then asolution of 25 g (140 mmol) of ethyl 3-bromopropionate in 10 mL ofdimethylformamide was added dropwise. The reaction mixture was stirredovernight slowly warming to ambient temperature, then concentrated. Theresidue was partitioned between ethyl acetate and was extracted withethyl acetate. The combined organic extracts were washed with brine,dried over sodium sulfate, filtered and concentrated. The residue wasabsorbed onto a silica pad and chromatographed on silica gel using agradient of 20-70% ethyl acetate/hexanes to yield 22.71 g (76%) of thedesired product as a yellow oil: ¹H-NMR is consistent with structure; MS(FD) 213 (M+); Anal. Calc'd for C₈H₁₁N₃O₄: C, 45.07; H, 5.20; N, 19.71.Found: C, 45.08; H, 5.18; N, 19.42.

To a solution of the product of Preparation 283, 22.46 g (100 mmol) in100 mL of tetrahydrofuran and 100 mL of ethanol was added 100 mL of 5Nsodium hydroxide. The mixture was stirred at ambient temperature for 1h, then acidified to pH=2.5 with 5N hydrochloric acid and extracted withethyl acetate. The combined organic extracts were washed with brine,dried over sodium sulfate, filtered and concentrated to yield 7.8 g(42%) of the desired product as an orange oil: ¹H-NMR is consistent withstructure; MS (FD) 185 (M+).

To a solution of the product of Preparation 284, 5.3 g (29 mmol),pyrrolidine, 2.4 mL (29 mmol) and 1-hydroxybenzotriazole, 4.3 g (32mmol) in 50 mL of dimethylformamide was added 6.6 g (32 mmol) ofdicyclohexylcarbodiimide. The reaction mixture was stirred overnight atambient temperature and was then concentrated in vacuo. The residue waspartitioned between ethyl acetate and water and was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The residue was absorbedonto a silica pad and chromatographed on silica gel using a gradient of2.5-5% methanol/chloroform as eluant to yield 0.69 g (10%) of thedesired product as a yellow solid: ¹H-NMR is consistent with structure;MS (FD) 238 (M+); Anal. Calc'd for C₁₀H₁₄N₄O₃: C, 50.41; H, 5.92; N,23.52. Found: C, 50.59; H, 5.75; N, 23.47.

To a slurry of 0.66 g of 10% palladium on carbon in 15 mL of ethylacetate was added a solution of 0.66 g (2.8 mmol) of the product ofPreparation 285 in 6 mL of dichloromethane and 15 mL of ethanol. Themixture was hydrogenated at 40 psi of hydrogen for 40 min and filteredthrough celite and concentrated. The residue was dissolved in 30 mL ofdimethylformamide. To this solution was added 1.1 g (2.8 mmol) of theproduct of Preparation 1d, 0.42 g (3.1 mmol) of 1-hydroxybenzotriazoleand 0.63 g (3.1 mmol) of dicyclohexylcarbodiimide. The reaction wasstirred overnight at ambient temperature, filtered and concentrated. Theresidue was partitioned between ethyl acetate and water and wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated. Theresulting residue was chromatographed on silica gel using a gradient ofchloroform to 3% methanol/chloroform as eluant to yield 0.67 g (42%) ofthe desired product as a tan foam: ¹H-NMR is consistent with structure;MS (FD) 570.2 (M+); Anal. Calc'd for C₂₉H₄₂N₆O₆: C, 61.03; H, 7.42; N,14.73. Found: C, 60.94; H, 7.26; N, 14.55.

Example 155

To a solution of the product of Preparation 286, 0.6 g (1.1 mmol) in 12mL of dichloromethane was added 4 mL of trifluoroacetic acid. Thereaction mixture was stirred for 2 h, quenched with solid sodiumcarbonate and extracted with chloroform. The combined organic extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated. To a solution of the residue in 10 mL of ethyl acetate wasadded 10 mL of ether.hydrochloric acid. The resultant slurry wasconcentrated to yield 0.52 g (94%) of the desired product as a tan foam:¹H-NMR is consistent with structure; MS (FD) 471 (M+1); Anal. Calc'd forC₂₄H₃₄N₆O₄.2.25HCl: C, 52.16; H, 6.61; N, 15.21. Found: C, 52.48; 6.87;N, 14.81.

Ethyl-4-bromobutyrate (18.4 mL, 156 mmol), 4-nitroimidazole (17.6 g, 130mmol), sodium hydride (6.24 g, 156 mmol), dimethylformamide (400 mL), asdescribed Preparation 283 gave 23.4 g (80%) of the desired product as ayellow oil: ¹H-NMR is consistent with structure; MS (FD) 227 (M+); Anal.Calc'd for C₉H₁₃N₃O₄: C, 47.58; H, 5.77; N, 18.49. Found: C, 47.48; H,5.50; N, 18.30.

Reaction of the product of Preparation 287 (22.84 g, 100 mmol), 5Nsodium hydroxide (100 mL), tetrahydrofuran (100 mL), ethanol (100 mL),as described in Preparation 284 gave 9.8 g (50%) of the desired productas an orange solid: ¹H-NMR is consistent with structure; MS (FD) 200.1(M+); Anal. Calc'd for C₇H₉N₃O₄: C, 42.22; H, 4.56; N, 21.10. Found: C,41.97; H, 4.63; N, 21.04.

Reaction of the product of Preparation 288 (4.87 g, 25 mmol),pyrrolidine (2.4 mL, 25 mmol), 1-hydroxybenzotriazole (3.7 g, 27.5mmol), dicyclohexylcarbodiimide (5.6 g, 27.5 mmol), dimethylformamide(50 mL), as described in Preparation 285, gave 0.65 g (11%) of thedesired product as a tan oil: ¹H-NMR is consistent with structure; MS(FD) 252 (M+); Anal. Calc'd for C₁₁ _(H) ₁₆N₄O₃: C, 52.37; H, 6.39; N,22.21. Found: C, 52.59; H, 6.50; N, 22.44.

Reaction of the product of Preparation 289 (0.6 g, 2.4 mmol), 10%palladium on carbon (0.3 g), dichloromethane (6 mL), ethyl acetate (20mL), absolute ethanol (20 mL); 386979 (0.91 g, 2.4 mmol),1-hydroxybenzotriazole (0.36 g, 2.64 mmol), dicyclohexylcarbodiimide(0.54 g, 2.64 mmol), dimethylformamide (40 mL), as described inPreparation 286 gave 0.69 g (50%) of the desired product as a tan oil:¹H-NMR is consistent with structure; MS (FD) 585.4 (M+); Anal. Calc'dfor C₃₀H₄₄N₆O₆: C, 61.63; H, 7.58; N, 14.37. Found: C, 61.35; H, 7.50;N, 14.30.

Example 156

Reaction of the product of Preparation 290 (0.65 g, 1.1 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 155 gave 0.58 g (98%) of the desired hydrochloric acid salt asan oil: ¹H-NMR is consistent with structure; MS (FD) 484 (M+); Anal.Calc'd for C₂₅H₃₆N₆O₄.2.3HCl: C, 52.82; H, 6.79; N, 14.78. Found: C,53.01; H, 6.88; N, 14.40.

Reaction of ethyl-5-bromovalerate (25 g, 120 mmol), 4-nitroimidazole(16.3 g, 144 mmol), sodium hydride (5.8 g, 144 mol), dimethylformamide(400 mL), as described Preparation 283 gave 21.9 g (75%) of the desiredproduct as a colorless oil: ¹H-NMR is consistent with structure; MS (FD)241.1 (M+); Anal. Calc'd for C₁₀H₁₅N₃O₄: C, 49.79; H, 6.27; N, 17.42.Found: C, 49.63; H, 6.16; N, 17.22.

Reaction of the product of Preparation 291 (21.08 g, 87 mmol), 5N sodiumhydroxide (100 mL), tetrahydrofuran (100 mL), ethanol (100 mL), asdescribed in Preparation 284 gave 11.9 g (64%) of the desired product asa tan solid: ¹H-NMR is consistent with structure; MS (FD) 214 (M+);

Anal. Calc'd for C₈H₁₁N₃O₄: C, 45.07; H, 5.20; N, 19.71.

Found: C, 44.89; H, 4.92; N, 19.44.

Reaction of the product of Preparation 292(9.9 g, 46.4 mmol),pyrrolidine (4 mL, 46.4 mmol), 1-hydroxybenzotriazole (7.0 g, 51.0mmol), dicyclohexylcarbodiimide (10.6 g, 51.0 mmol)), triethylamine(3.23 mL, 46.4 mmol), as described in Preparation 285 gave 8.4 g (69%)of the desired product as a colorless oil: ¹H-NMR is consistent withstructure; MS (FD) 266 (M+); Anal. Calc'd for C₁₂H₁₈N₄O₃: C, 54.12; H,6.81; N, 21.04. Found: C, 54.35; H, 6.91; N, 20.91.

Reaction of the product of Preparation 293 (1.0 g, 3.8 mmol), 10%palladium on carbon (0.5 g), dichloromethane (5 mL), ethyl acetate (10mL), ethanol (20 mL), the product of Preparation 1d (1.45 g, 3.8 mmol),1hydroxybenzotriazole (0.56 g, 4.2 mmol), dicyclohexylcarbodiimide (0.86g, 1.1 mmol), dimethylformamide (40 mL), as described in Preparation 286gave 0.8 g (35%) of the desired product as a yellow oil: ¹H-NMR isconsistent with structure; MS (FD) 598.2 (M+).

Example 157

Reaction of the product of Preparation 294 (0.75 g, 1.2 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 155 gave 0.57 g (100%) of the desired product as thehydrochloric acid salt as a white solid: ¹H-NMR is consistent withstructure; MS (FD) 499 (M+).

Reaction of N-(2-chloroethyl)morpholine hydrochloride (6.9 g, 37.0mmol), 4-nitroimidazole (5.0 g, 44.0 mmol), sodium hydride (3.27 g, 80.7mmol), dimethylformamide (150 mL), as described in Preparation 283 gave1.1 g (13%) of the desired product as a yellow solid: ¹H-NMR isconsistent with structure; MS (FD) 226.1 (M+1); Anal. Calc'd forC₉H₁₄N₄O₃: C, 47.78; H, 6.24; N, 24.77. Found: C, 48.01; H, 6.13; N,.24.56.

Reaction of the product of Preparation 295 (0.6 g, 2.6 mmol), 10%palladium on carbon (0.6 g), ethyl acetate (20 mL), ethanol (10 mL), theproduct of Preparation 1d (1.0 g, 2.6 mmol), 1-hydroxybenzotriazole (0.4g, 2.9 mmol), dicyclohexylcarbodiimide (0.6 g, 2.9 mmol),dimethylformamide (40 mL), as described in Preparation 286 gave 0.34 g(24%) of the desired product as a yellow foam: ¹H-NMR is consistent withstructure; MS (FD) 558 (M+1).

Example 158

Reaction of the product of Preparation 296 (0.14 g, 0.25 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 155 gave 0.13 g (100%) of the desired product as thehydrochloric acid salt as a white solid: 1H-NMR is consistent withstructure; MS (FD) 458.2 (M+).

To a solution of 4-nitroimidazole, 4.6 g (40 mmol) andbromodiphenylmethane, 10.0 g (40 mmol) in 150 mL of dimethylformamidewas added 16.6 g (120 mmol) of potassium carbonate. The reaction mixturewas stirred overnight at ambient temperature, filtered and concentrated.The residue was partitioned between ethyl acetate and water and wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated. Theresulting crude material was absorbed onto a silica pad andchromatographed on silica gel using 25-60% ethyl acetates/hexanes aseluant to yield 3.2 g (27%) of the desired product as a clear oil:¹H-NMR is consistent with structure; MS (ion spray) 280 (M+1).

To a slurry of 0.8 g of 10% palladium on carbon in 30 mL oftetrahydrofuran was added a solution of 1.2 g (4.3 mmol) of the productof Preparation 297 in 40 mL of tetrahydrofuran. The mixture washydrogenated at 40 psi of hydrogen for 1 h and filtered through celite.To this solution was added 1.64 g (4.3 mmol) of Preparation 4 fromExamples Part 1, 0.7 g (4.7 mmol) of 1-hydroxybenzotriazole and 1.04 g(4.7 mmol) of dicyclohexylcarbodiimide. The reaction was stirredovernight at ambient temperature, filtered and concentrated. Theresulting residue was chromatographed on silica gel using 4%methanol/chloroform as eluant to yield 1.57 g (60%) of the desiredproduct. ¹H-NMR is consistent with structure; MS (ion spray) 612.4(M+1);

Anal. Calc'd for C₃₅H₄₁N₅O₅: C, 68.72; H, 6.76; N, 11.45.

Found: C, 68.44; H, 6.72; N, 11.15.

Example 159

To a solution of the product of Preparation 298, 0.56 g (0.91 mmol) in 6mL of dichloromethane was added 2 mL of trifluoroacetic acid. Thereaction mixture was stirred for 2.5 h, then poured into a solution ofsaturated sodium carbonate and extracted with chloroform. The combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered and concentrated. The desired product was trituated with ethylacetate/hexanes to yield 0.45 g (96%) of the desired product as a tansolid: ¹H-NMR is consistent with structure; MS (ion spray) 512.6 (M+1);Anal. Calc'd for C₃₀H₃₃N₅O₃.0.2H₂O: C, 69.94; H, 6.53; N, 13.59. Found:C, 69.88; H, 6.36; N, 13.25.

To a solution of 4,4′-dimethoxybenzhydrol, 5.0 g (20 mmol),4-nitroimidazole, 2.31 g (20 mmol) and triphenylphosphine, 5.3 g (20mmol) in 200 mL of tetrahydrofuran at 0° C. was added 5.0 mL (32 mmol)of diethyl azodicarboxylate dropwise. The resulting mixture was slowlywarmed to ambient temperature, stirred overnight and concentrated. Theresidue was partitioned between ethyl acetate and water and extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried over sodium sulfate, filtered and concentrated. The residuewas absorbed onto a silica pad and chromatographed on silica gel using20-40% ethyl acetates/hexane as eluant. The resulting residue waschromatographed on silica gel using 3% methanol/chloroform as eluant toyield 4.92 g (72%) of the desired product as a yellow oil: ¹H-NMR isconsistent with structure; MS (ion spray) 340 (M+1); Anal. Calc'd forC₁₈H₁₇N₃O₄.0.3H₂O: C, 62.71; H, 5.15; N, 12.19. Found: C, 62.48; H,4.83; N, 11.84.

Reaction of the product of Preparation 299 (1.8 g, 5.3 mmol), 10%palladium on carbon (1.0 g), tetrahydrofuran (60 mL), 386979 (2.0 g, 5.3mmol), 1-hydroxybenzotriazole (0.8 g, 5.83 mmol),dicyclohexylcarbodiimide (1.2 g, 5.83 mmol), as described in Preparation159 gave 1.3 g (36%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (ions spray) 672.7 (M+1);

Anal. Calc'd for C₃₇H₄₅N₅O₇: C, 66.15; H, 6.75; N, 10.43.

Found: C, 66.29; H, 6.82; N, 10.63.

Example 160

Reaction of the product of Preparation 300 (1.24 g, 1.8 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inExample 159, Chromatographed over silica gel (5% methanol/chloroform) toyield 0.73 g (69%) of the desired product as a white foam: ¹H-NMR isconsistent with structure; MS (ion spray) 572.4 (M+1);

Anal. Calc'd for C₃₂H₃₇N₅O₅: C, 67.23; H, 6.52; N, 12.25.

Found: C, 67.05; H, 6.59; N, 11.97.

To a slurry of sodium hydride, 2.64 g (66.0 mmol) in 300 mL ofdimethylformamide at 0° C. was added 7.4 g (66.0 mmol) of4-nitroimidazole. After stirring for 20 min at 0° C., 15.0 g (55.0 mmol)of desyl bromide was added. The reaction mixture was stirred 65 h, as itwarmed to ambient temperature and was concentrated. The residue waspartitioned between ethyl acetate and water and was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The resulting residuewas chromatographed on silica gel using a gradient of chloroform to 5%methanol/chloroform as eluant to yield 10.1 g (60%) of the desiredproduct as a yellow oil which solidifies upon standing. ¹H-NMR isconsistent with structure; MS (ion spray) 307.1 (M+1);

Anal. Calc'd for C₁₇H₁₃N₃O₃: C, 66.44; H, 4.26; N, 13.67.

Found: C, 66.31; H, 4.22; N, 13.39.

To a slurry of 0.3 g of 10% palladium on carbon in 20 mL oftetrahydrofuran was added a solution of 0.8 g (2.6 mmol) of the productof Preparation 301 in 20 mL of tetrahydrofuran. The mixture washydrogenated at 40 psi of hydrogen for 1 h and filtered through celite.To this solution was added 1.0 g (2.6 mmol) of the product ofPreparation 1d, 0.4 g (2.9 mmol) of 1-hydroxybenzotriazole and 0.6 g(2.9 mmol) of dicyclohexylcarbodiimide. The reaction was stirredovernight at ambient temperature, filtered and concentrated. Theresulting residue was chromatographed on silica gel using a gradientfrom chloroform to 5% methanol/chloroform as eluant to yield 1.3 g (76%)of the desired product. ¹H-NMR is consistent with structure; MS (FD)639.4 (M+); Anal. Calc'd for C₃₆H₄₁N₅O₆: C, 65.74; H, 6.59; N, 10.65.Found: C, 65.91; H, 6.21; N, 10.67.

Example 161

To a solution of the product of Preparation 302, 1.0 g (1.56 mmol) in 12mL of dichloromethane was added 4 mL of trifluoroacetic acid. Thereaction mixture was stirred for 1.5 h, then quenched with solid sodiumcarbonate and extracted with chloroform. The combined organic extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was dissolved in ethyl acetate andether.hydrochloric acid was added. The mixture was concentrated to yield0.68 g (71%) of the desired product as a tan solid: ¹H-NMR is consistentwith structure; MS (FD) 539 (M+); Anal. Calc'd for C₃₁H33N₅O₄.2HCl: C,60.78; H, 5.76; N, 11.43. Found: C, 60.51; H, 5.84; N, 11.12.

To a slurry of desoxyanisoin, 20 g (78 mmol) in 200 mL of carbontetrachloride at 0° C. was added 4 mL (78 mmol) of bromine, dropwiseover 30 min. The reaction mixture was stirred overnight while slowlywarming to ambient temperature, then concentrated. The residue wasabsorbed onto a silica pad and chromatographed on silica gel using agradient of 10-30% ethyl acetate/hexanes as eluant to yield 18 g (69%)of the desired product as a white solid: ¹H-NMR is consistent withstructure; MS (ion spray) 335, 337 (M+1).

Reaction of the product of Preparation 303 (7.0 g, 20.0 mmol),4-nitroimidazole (2.34 g, 20.0 mmol), sodium hydride (1.0 g, 24.0 mmol),dimethylformamide (100 mL), as described in Preparation 301. The crudematerial was absorbed onto a silica pad and chromatographed over silicagel using a gradient of 30-80% ethyl acetate/hexanes to yield 2.8 g(38%) of the desired product as a tan foam: ¹H-NMR is consistent withstructure; MS (ion spray) 366.1 (M+1); Anal. Calc'd for C₁₉H₁₇N₃O₅: C,62.12; H, 4.66; N, 11.44. Found: C, 62.05; H, 4.55; N, 11.57.

Reaction of the product of Preparation 304 (1.5 g, 4.1 mmol), 10%palladium on carbon (1.0 g), tetrahydrofuran (40 mL), the product ofPreparation 1d (1.56 g, 4.1 mmol), 1-hydroxybenzotriazole (0.61 g, 4.51mmol), dicyclohexylcarbodiimide (0.93 g, 4.51 mmol), as in described inPreparation 302. The residue was chromatographed on silica gel using 3%methanol/chloroform as eluant to yield 1.95 g (68%) of the desiredproduct as a tan foam: ¹H-NMR is consistent with structure; MS (ionspray) 700.8 (M+1); Anal. Calc'd for C₃₈H₄₅N₅O₈: C, 65.22; H, 6.48; N,10.01. Found: C, 65.05; H, 6.20; N, 10.25.

Examples 162 and 163

Reaction of the product of Preparation 305 (1.85 g, 2.6 mmol),trifluoroacetic acid (10 mL), dichloromethane (24 mL), as in describedin Example 161, gave 1.56 g (88%) of the desired product as a product asthe hydrochloric acid salt. ¹H-NMR is consistent with structure; MS (ionspray) 599.2 (M+1); Anal. Calc'd for C₃₃H₃₇N₅O₆.2HCl: C, 58.93; H, 5.84;N, 10.41. Found: C, 59.05; H, 5.87; N, 10.43. Resolution of thediastereomers (0.21 g, 0.38 mmol) by chiral HPLC gave the respectiveisomers which were individually treated with a saturated solution ofhydrochloric acid in diethyl ether to give the desired products:

Example 162. (Isomer 1) 0.104 g (40%); ¹H-NMR is consistent withstructure; t_(R)=9.45 min; MS (ion spray) 600.3 (M+1); Anal. Calc'd forC₃₃H₃₇N₅O₆.2HCl: C, 58.93; H, 5.84; N, 10.41. Found: C, 58.66; H, 5.80;N, 10.20.

Example 163. (Isomer 2) 0. 066 g (25%); ¹H-NMR is consistent withstructure; t_(R)=12.93 min; MS (ion spray) 600.3 (M+1); Anal. Calc'd forC₃₃H₃₇N₅O₆.2.3HCl: C, 57.99; H, 5.80; N, 10.25. Found: C, 57.94; H,5.80; N, 10.12.

To a slurry of 4-nitroimidazole, 10.0 g (89 mmol) in 30 mL of glacialacetic acid was slowly added 10 mL of fuming nitric acid. To thismixture was added 20 mL of acetic anhydride at a rate such that thetemperature remained below 50° C. The reaction mixture was stirred forone hour then poured into 300 g of ice/water. A white solid precipitatedout over a period of 30 min. The solid was filtered and dried to yield6.8 g of the desired product. The filtrate was extracted withdichloromethane. The combined organic extracts were washed withsaturated sodium bicarbonate and water, then dried over sodium sulfate,filtered and concentrated to yield an additional 5.1 g of the desiredwhite solid, affording a total of 11.9 g (85%) of the desired product.¹H-NMR is consistent with structure; MS (FD) 159 (M+);

Anal. Calc'd for C₃H₂N₄O₄.0.3H₂O: C, 22.04; H, 1.60; N, 34.27 Found: C,22.35; H, 1.52; N, 33.87.

To a slurry of 9-aminofluorene hydrochloride, 2.1 g (10.0 mmol) in 20 mLof methanol and 20 mL of water at 0° C. was added 0.8 g (10.0 mmol) ofsodium bicarbonate. After stirring for 10 min at 0° C., 1.5 g (10.0mmol) of the product of Preparation 306 was added. The reaction mixturewas stirred overnight, slowly warming to ambient temperature, thenconcentrated. The residue was partitioned between ethyl acetate andwater and extracted with ethyl acetate. The combined organic extractswere washed with brine, dried over sodium sulfate and concentrated. Theresidue was absorbed onto a silica pad and chromatographed on silica gelusing a gradient of 25-80% ethyl acetate/hexanes as eluant to yield 2.39g (88%) of the desired product as a tan solid: ¹H-NMR is consistent withstructure; MS (ion spray) 276.2 (M+1);

Anal. Calc'd for C₁₆H₁₁N₃O₂: C, 69.31; H, 4.00; N, 15.15.

Found: C, 69.53; H, 4.08; N, 14.93.

To a slurry of 0.95 g of 10% palladium on carbon in 30 mL oftetrahydrofuran was added a solution of 1.1 g (4.0 mmol) of the productof Preparation 307 in 30 mL of tetrahydrofuran. The mixture washydrogenated at 40 psi of hydrogen for 1 h and filtered through celite.To this solution was added 1.5 g (4.0 mmol) of the product ofPreparation 1d, 0.6 g (4.4 mmol) of 1-hydroxybenzotriazole and 0.9 g(4.4 mmol) of dicyclohexylcarbodiimide. The reaction was stirredovernight at ambient temperature, filtered and concentrated. The residuewas slurried in ethyl acetate, filtered and water was added. The mixturewas extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried over sodium sulfate, filtered and concentrated.The resulting residue was chromatographed on silica gel using 5%methanol/chloroform as eluant to yield 1.16 g (48%) of the desiredproduct. ¹H-NMR is consistent with structure; MS (ion spray) 610 (M+1);Anal. Calc'd for C₃₅H₃₉N₅O₅: C, 68.95; H, 6.59; N, 11.49. Found: C,68.83; H, 6.46; N, 11.27.

Example 164

To a solution of the product of Preparation 308, 1.1 g (1.8 mmol) in 6mL of dichloromethane was added 2 mL of trifluoroacetic acid. Thereaction mixture was stirred for 3 h, then poured into a solution ofsaturated sodium carbonate. The mixture was extracted with chloroform.The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was dissolved in ethylacetate and ether/hydrochloric acid was added. The mixture wasconcentrated to yield 0.9 g (90%) of the desired product as a pinksolid: ¹H-NMR is consistent with structure; MS (ion spray) 510.4 (M+1);Anal. Calc'd for C₃₀H₃₁N₅O₃.2HCl: C, 61.86; H, 5.71; N, 12.02. Found: C,61.70; H, 5.78; N, 11.86.

Reaction of 2,2-diphenylethylamine (2.5 g, 12.7 mmol), sodiumbicarbonate (1.07 g, 12.7 mmol), the product of Preparation 306 (2.0 g,12.7 mmol), methanol (20 mL), water (10 mL), as described in Preparation307 gave 2.75 g (74%) of the desired product as a tan solid: ¹H-NMR isconsistent with structure; MS (ion spray) 294.2 (M+1).

Reaction of the product of Preparation 309 (1.0 g, 3.4 mmol), 10%palladium on carbon (1.2 g), tetrahydrofuran (40 mL), the product ofPreparation 1d (1.3 g, 3.4 mmol), 1-hydroxybenzotriazole (0.51 g, 3.74mmol), dicyclohexylcarbodiimide (0.8 g, 3.74 mmol), as in ExamplePreparation 308. 1.42 g (67%) of the desired product as a tan foam:¹H-NMR is consistent with structure; MS (ion spray) 626.3 (M+1); Anal.Calc'd for C₃₆H₄₃N₅O₅: C, 69.10; H, 6.93; N, 11.19. Found: C, 68.92; H,6.70; N, 11.21.

Example 165

Reaction of the product of Preparation 310 (1.37 g, 2.2mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as described inExample 164—426737 gave 1.14 g (87%) of the desired product as a tansolid: ¹H-NMR is consistent with structure; MS (ion spray) 526 (M+1);

Anal. Calc'd for C₃₁H₃₅N₅O₃.2.2HCl: C, 61.46; H, 6.19; N, 11.56. Found:C, 61.72; H, 5.95; N, 11.11.

To a slurry of 2-aminoindan hydrochloride, 2.0 g (12.7 mmol) in 20 mL ofmethanol and 10 mL of water at 0° C. was added 1.4 g (16.4 mmol) ofsodium bicarbonate. After stirring for 10 min at 0° C., 2.0 g (12.7mmol) of the product of Preparation 306 was added. The reaction mixturewas stirred overnight, slowly warming to ambient temperature, thenconcentrated. The residue was partitioned between ethyl acetate andwater and extracted with ethyl acetate. The combined organic extractswere washed with brine, dried over sodium sulfate and concentrated. Theresidue was absorbed onto a silica pad and chromatographed on silica gelusing a gradient of 50-80% ethyl acetate/hexanes as eluant to yield 1.91g (66%) of the desired product as a tan solid: ¹H-NMR is consistent withstructure; MS (ion spray) 230.2 (M+1);

Anal. Calc'd for C₁₂H₁₁N₃O₂: C, 62.88; H, 4.84; N, 18.33.

Found: C, 63.28; H, 4.90; N, 17.89.

To a slurry of 1.3 g of 10% palladium on carbon in 30 mL oftetrahydrofuran was added a solution of 1.2 g (5.3 mmol) of the productof Preparation 311 in 30 mL of tetrahydrofuran. The mixture washydrogenated at 40 psi of hydrogen for 40 min and filtered throughcelite. To this solution was added 2.0 g (5.3 mmol) of the product ofPreparation 1d, 0.8 g (5.8 mmol) of 1-hydroxybenzotriazole and 1.2 g(5.8 mmol) of dicyclohexylcarbodiimide. The reaction was stirredovernight at ambient temperature, filtered and concentrated. The residuewas slurried in ethyl acetate, filtered and water was added. The mixturewas extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried over sodium sulfate, filtered and concentrated.The resulting residue was chromatographed on silica gel using 3%methanol/chloroform as eluant to yield 1.38 g (486) of the desiredproduct: ¹H-NMR is consistent with structure; MS (ion spray) 562.4(M+1); Anal. Calc'd for C₃₁H₃₉N₅O₅.0.1CHCl3: C, 65.12; H, 6.87; N,12.21. Found: C, 65.39; H, 7.18; N, 11.97.

Example 166

To a solution of the product of Preparation 312, 1.4 g (2.5 mmol) in 12mL of dichloromethane was added 4 mL of trifluoroacetic acid. Thereaction mixture was stirred for 2 h, then concentrated. The residue waspartitioned between ethyl acetate and saturated sodium carbonate and wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated. Theresidue was dissolved in ethyl acetate and ether.hydrochloric acid wasadded. The mixture was concentrated to yield 1.2 g (90%) of the desiredproduct as a yellow solid: ¹H-NMR is consistent with structure; MS (ionspray) 462.4 (M+1);

Anal. Calc'd for C₂₆H₃₁N₅O₃.2HCl: C, 57.99; H, 6.93; N, 12.01. Found: C,57.87; H, 6.82; N, 12.73.

To a slurry of 1-aminoindan, 1.25 mL (10.0 mmol) in 20 mL of methanoland 20 mL of water at 0° C., was added 1.5 g (10.0 mmol) of the productof Preparation 306. The reaction mixture was stirred overnight, slowlywarming to ambient temperature and concentrated. The residue waspartitioned between ethyl acetate and water and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The residue was absorbedonto a silica pad and chromatographed on silica gel using 30-80% ethylacetate/hexanes as eluant to yield 1.13 g (49%) of the desired productas a tan oil: ¹H-NMR is consistent with structure; MS (ion spray) 230.2(M+1).

To a slurry of 1.0 g of 10% palladium on carbon in 20 mL. oftetrahydrofuran was added a solution of 1.07 g (4.7 mmol) of the productof Preparation 313 in 20 mL of tetrahydrofuran. The mixture washydrogenated at 40 psi of hydrogen for 30 min and filtered throughcelite. To this solution was added 1.8 g (4.7 mmol) of the product ofPreparation 1d, 0.7 g (5.2 mmol) of 1-hydroxybenzotriazole and 1.06 g(5.2 mmol) of dicyclohexylcarbodiimide. The reaction was stirredovernight at ambient temperature, filtered and concentrated. The residuewas dissolved in ethyl acetate, filtered, then water was added. Themixture was extracted with ethyl acetate. The combined organic extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated. The resulting residue was chromatographed on silica gelusing 3% methanol/chloroform as eluant to yield 0.99 g (38%) of thedesired product: ¹H-NMR is consistent with structure; MS (ion spray) 562(M+1); Anal. Calc'd for C₃₁H₃₉N₅O₅: C, 66.29; H, 7.00; N, 12.47. Found:C, 66.05; H, 7.12; N, 12.58.

Example 167

To a solution of the product of Preparation 314, 0.97 g (1.7 mmol) in 6mL of dichloromethane was added 2 mL of trifluoroacetic acid. Thereaction mixture was stirred for 2 h, then poured into a solution ofsaturated sodium carbonate. The mixture was extracted with chloroform.The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was dissolved in ethylacetate and a saturated solution of hydrochloric acid in diethyl etherwas added. The resulting mixture was concentrated to yield 0.73 g (76%)of the desired mixture of isomers as a white solid: ¹H-NMR is consistentwith structure; MS (ion spray) 462.4 (M+1); Anal. Calc'd forC₂₆H₃₁N₅O₃.2.3HCl: C, 57.26; H, 6.15; N, 12.84. Found: C, 57.53; H,6.04; N, 12.57.

Reaction of (1S,2R)-(−)-cis-1-Amino-2-indanol (0.9 g, 6.3 mmol), sodiumbicarbonate (0.53 g, 6.3 mmol), the product of Preparation 306, (1.0 g,6.3 mmol) in methanol (10 mL) and water (5 mL),as described inPreparation 311 gave 1.02 g (66%) of the desired product as a tan foam:¹H-NMR is consistent with structure; MS (ion spray) 246.3 (M+1).

To a solution of the product of Preparation 315, 2.33 g (9.5 mmol) andimidazole, 2.0 g (36.9 mmol) in 100 mL of dimethylformamide was added1.86 g (12.3 mmol) of t-butyldimethylsilyl chloride. The reactionmixture was stirred overnight at ambient temperature then concentrated.The residue was partitioned between ethyl acetate and water and wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated. Theresidue was chromatographed over silica gel using 50% ethylacetate/hexanes as eluent to yield 3.07 g (90%) of the desired productas a tan oil: ¹H-NMR is consistent with structure; MS (ion spray) 360.2(M+1); Anal. Calc'd for C₁₈H₂₅N₃O₃Si: C, 60.14; H, 7.01; N, 11.69.Found: C, 60.37; H, 6.92; N, 11.43.

Reaction of the product of Preparation 316 (1.5 g, 4.2 mmol), 10%palladium on carbon (1.0 g), tetrahydrofuran (80 mL), the product ofPreparation 1d, (1.6 g, 4.2 mmol), 1-hydroxybenzotriazole (0.63 g, 4.6mmol), dicyclohexylcarbodiimide (0.95 g, 4.6 mmol), as described inPreparation 314 gave 0.72 g (25%) of the desired product as a reddishfoam: ¹H-NMR is consistent with structure; MS (ion spray) 692.1 (M+1);Anal. Calc'd for C₃₇H₅₃N₅O₆Si: C, 64.34; H, 7.72; N, 10.12. Found: C,64.14; H, 7.65; N, 10.05.

Example 168

A solution of the product of Preparation 317, 0.65 g (0.94 mmol) in 10mL of a saturation solution of hydrochloric acid in acetic acid wasstirred at ambient temperature. After 1.5 h, the solution wasconcentrated. The residue was partitioned between ethyl acetate andsaturated sodium bicarbonate and was extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over sodiumsulfate and concentrated. The residue was chromatographed on silica gelusing a gradient of 5-10% methanol/chloroform/ammonia as eluant to yieldthe desired product as the free base. The resulting foam was dissolvedin ethyl acetate and a saturated solution of hydrochloric acid indiethyl ether was added. The resulting slurry was concentrated to yield0.18 g (35%) of the desired product as a white solid: ¹H-NMR isconsistent with structure; MS (ion spray) 478.3 (M+1); Anal. Calc'd forC₂₆H₃₁N₅O₄.2.5HCl: C, 47.85; H, 5.53; N, 10.73. Found: C, 48.08; H,5.17; N, 10.40.

To a solution of the product of Preparation 315, 1.71 g (7.0 mmol) andtriethylamine, 2.2 mL (15.6 mmol) in 80 mL of dichloromethane at 0° C.was added 0.9 mL (12.6 mL) of acetyl chloride. The reaction mixture wasstirred 2.5 h at 0° C., then was quenched with saturated sodiumbicarbonate. The mixture was extracted with ethyl acetate. The combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered and concentrated. The residue was absorbed onto a silica padand chromatographed on silica gel using a gradient of 30-80% ethylacetate/hexanes as eluant to yield 1.06 g (53%) of the desired productas a yellow oil: ¹H-NMR is consistent with structure; MS (ion spray)288.0 (M+1);

Anal. Calc'd for C₁₄H₁₃N₃O₄: C, 58.53; H, 4.56; N, 14.63.

Found: C, 58.78; H, 4.58; N, 14.36.

Reaction of the product of Preparation 318 (1.0 g, 3.5 mmol), 10%palladium on carbon (2.0 g), tetrahydrofuran (60 mL), the product ofPreparation 1d, (1.33 g, 3.5 mmol), 1-hydroxybenzotriazole (0.52 g, 3.9mmol), dicyclohexylcarbodiimide (0.8 g, 3.9 mmol), described inPreparation 314 gave 0.53 g (25%) of the desired product as a tan foam:¹H-NMR is consistent with structure; MS (ion spray) 620.4 (M+1); Anal.Calc'd for C₃₃H₄₁N₅O₇.0.15CHCl₃: C, 62.44; H, 6.50; N, 10.98. Found: C,62.42; H, 6.51; N, 11.16.

Example 169

A solution of the product of Preparation 319, 0.43 g (0.7 mmol) in 8 mLof a saturated solution of hydrochloric acid in glacial acetic acid wasstirred for 1.5 h at ambient temperature then concentrated. The residuewas dissolved in toluene and concentrated to yield 0.26 g (61%) of thedesired product as a tan solid: ¹H-NMR is consistent with structure; MS(ion spray) 520.3 (M+1);

Anal. Calc'd for C₂₈H₃₃N₅O₅.2HCl: C, 56.76; H, 5.95; N, 1.82. Found: C,56.87; H, 6.07; N, 11.52.

To a solution of the product of Preparation 315, 1.36 g (5.6 mmol) in 50mL of dichloromethane was added 1.09 g (6.72 mmol) of1,1′-carbonyldiimidazole. The reaction mixture was stirred overnight atambient temperature then 3.3 mL (28 mmol) of 4-methylpiperidine wasadded. The reaction mixture was stirred overnight, washed with a 0.1Naqueous solution of hydrochloric acid, brine, dried over sodium sulfate,filtered and concentrated. The residue was chromatographed on silica gelusing a gradient of chloroform to 1% methanol/chloroform as eluant toyield 1.4 g (67%) of the desired product as a tan foam: ¹H-NMR isconsistent with structure; MS (ion spray) 371.1 (M+1); Anal. Calc'd forC₁₉H₂₂N₄O₄: C, 61.61; H, 5.99; N, 15.13. Found: C, 61.95; H, 6.01; N,14.95.

Reaction of the product of Preparation 320 (0.87 g, 2.3 mmol), 10%palladium on carbon (2.0 g), tetrahydrofuran (80 mL), the product ofPreparation 1d, (0.9 g, 2.3 mmol), 1-hydroxybenzotriazole (0.35 g, 2.53mmol), dicyclohexylcarbodiimide (0.52 g, 2.53 mmol), as described inPreparation 314, gave 0.23 g (14%) of the desired product as a tan foam:¹H-NMR is consistent with structure; MS (ion spray) 703.6 (M+1); Anal.Calc'd for C₃₈H₅₀N₆O₇.0.15CHCl₃: C, 63.57; H 7.01; N, 11.66. Found: C,63.60; H, 7.32; N, 11.31.

Example 170

To a solution of the product of Preparation 321, 0.21 g (0.3 mmol) in 6mL of dichloromethane was added 2 mL of trifluoroacetic acid. Themixture was stirred 40 min at ambient temperature then concentrated. Theresulting residue was partitioned between ethyl acetate and saturatedsodium bicarbonate and extracted with ethyl acetate. The combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered and concentrated. The crude product was chromatographed onsilica gel using 10% methanol/chloroform as eluant. To a solution of theproduct in chloroform was added a saturates solution of hydrochloricacid in diethyl ether. The slurry was concentrated to yield the desiredproduct as a white solid: ¹H-NMR is consistent with structure; MS (ionspray) 603.4 (M+1); Anal. Calc'd for C₃₃H₄₂N₆O₅.2.3HCl: C, 57.73; H,6.50; N, 12.24. Found: C, 57.80; H, 6.34; N, 12.15.

Reaction of (1R,2S)-(+)-1-amino-2-indanol (3.8 g, 26.0 mmol), sodiumbicarbonate (2.2 g, 26.0 mmol), the product of Preparation 306. (4.0 g,26.0 mmol), methanol (28 mL), water (12 mL), as in Preparation 313 gave4.0 g (63%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (ion spray) 246.3 (M+1); Anal. Calc'd for C₁₂H11N₃O₃:C, 58.77; H, 4.52; N, 17.13. Found: C, 58.68; H, 4.48; H, 17.00.

Reaction of the product of Preparation 322 (2.2 g, 9.0 mmol),1,1′-carbonyldiimidazole (1.73 g, 10.8 mmol), 4-methylpiperidine (5.3mL, 45.0 mmol), dichloromethane (80 mL), as described in Preparation320, gave 2.3 g (70%) of the desired product as an orange foam: ¹H-NMRis consistent with structure; MS (ion spray) 371.1 (M+1);

Anal. Calc'd for C₁₉H₂₂N₄O₄.0.15CHCl₃: C, 59.23; H, 5.75; N, 14.43.Found: C, 59.38; H, 5.87; N, 14.55.

Reaction of the product of Preparation 323 (2.22 g, 6.0 mmol), 10%palladium on carbon (3.0 g), tetrahydrofuran (60 mL), the product ofPreparation 1d, (2.3 g, 6.0 mmol), 1-hydroxybenzotriazole (0.9 g, 6.6mmol), dicyclohexylcarbodiimide (1.4 g, 6.6 mmol), as described inPreparation 314 gave 1.0 g (24%) of the desired product as a tan foam:¹H-NMR is consistent with structure; MS (ion spray) 703.6 (M+1); Anal.Calc'd for C₃₈H₅₀N₆O₇: C, 64.94; H, 7.17; N, 11.96. Found: C, 64.81; H,7.09; N, 11.83.

Example 171

Reaction of the product of Preparation 324 (0.97 g, 1.4 mmol),trifluoroacetic acid (4 mL), dichloromethane (12 mL), as in described inExample 170 gave 0.95 g (100%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (ion spray) 603.3 (M+1);

Anal. Calc'd for C₃₃H₄₂N₆O₅.2.3HCl: C, 57.73; H, 6.50; N, 12.24. Found:C, 57.46; H, 6.53; N, 11.90

Prepared as shown in Preparation 1 in Examples Part 4. ¹H-NMR consistentwith structure.

Reaction of the product of Preparation 4 from Examples Part 4 (0.4 g,1.4 mmol), 10% palladium on carbon (0.8 g), tetrahydrofuran (40 mL), theproduct of Preparation 1d, (0.53 g, 1.4 mmol), 1-hydroxybenzotriazole(0.21 g, 1.54 mmol), dicyclohexylcarbodiimide (0.32 g, 1.54 mmol), asdescribed in Preparation 314 gave 0.25 g (29%) of the desired product asa tan foam: ¹H-NMR is consistent with structure; MS (ion spray) 620.7(M+1); Anal. Calc'd for C₃₃H₄₁N₅O₇: C, 63.96; H, 6.67; N, 11.30. Found:C, 63.91; H, 6.72; N, 11.04.

Example 172

A solution of the product Preparation 326, 0.22 g (0.35 mmol) in 10 mLof a saturated solution of hydrochloric acid in glacial acetic acid wasstirred for 2 h at ambient temperature and then concentrated. Theresidue was dissolved in toluene and concentrated, then trituated withhexanes to yield 0.187 g (89%) of the desired product as a tan solid:¹H-NMR is consistent with structure; MS (ion spray) 520.3 (M+1); Anal.Calc'd for C₂₈H₃₃N₅O₅.2HCl: C, 56.76; H, 5.95; N, 11.82. Found: C,56.96; H, 6.06; N, 11.83.

To a solution of R-(−)-2-phenylglycinol, 2.75 g (20 mmol) in 20 mL ofmethanol and 10 mL of water at 0° C., was added 1.7 g (20 mmol) ofsodium bicarbonate. The reaction mixture was stirred for 20 min at 0°C., then 3.16 g (20 mmol) of the product of Preparation 306 was added.The residue was absorbed onto silica and chromatographed on silica gelusing 80% ethyl acetate/hexanes as eluant to yield 3.5 g (74%) of thedesired product as a colorless oil: ¹H-NMR is consistent with structure;MS (ion spray) 234 (M+1).

To a solution of the product of Preparation 327, 3.08 g (13.0 mmol),triethylamine, 2.4 mL (16.9 mmol) and 4-dimethylaminopyridine, 0.3 g(2.6 mmol) in 150 mL of dichloromethane at 0° C. was added 1.5 mL (15.6mmol) of acetic anhydride dropwise. The reaction mixture was stirredovernight slowly warming to ambient temperature, then concentrated. Theresidue was partitioned between ethyl acetate and saturated sodiumbicarbonate and extracted with ethyl acetate. The combined organicextracts were washed with brine, dried over sodium sulfate andconcentrated. The residue was chromatographed on silica gel using 80%ethyl acetate/hexanes as eluant to yield 3.4 g (95%) of the desiredproduct as a tan oil: ¹H-NMR is consistent with structure; MS (ionspray) 276.2 (95%); Anal. Calc'd for C₁₃H₁₃N₃O₄: C, 56.73; H, 4.76; N,15.27. Found: C, 56.46; H, 4.89; N, 15.17.

To a slurry of 4.0 g of 10% palladium on carbon in 60 mL oftetrahydrofuran was added a solution of 3.1 g (11.3 mmol) of the productof Preparation 328 in 60 mL of tetrahydrofuran. The mixture washydrogenated at 40 psi of hydrogen for 1.5 h and filtered throughcelite. To this solution was added 4.3 g (11.3 mmol) of the product ofPreparation 1d, 1.7 g (12.4 mmol) of 1-hydroxybenzotriazole and 2.6 g(12.4 mmol) of dicyclohexylcarbodiimide. The reaction was stirredovernight at ambient temperature, filtered and concentrated. Thereaction mixture was stirred overnight, slowly warming to ambienttemperature, then was concentrated. The residue was dissolved in ethylacetate, filtered, then water was added. The mixture was extracted withethyl acetate. The combined organic extracts were washed with brine,dried over sodium sulfate, filtered and concentrated. The resultingresidue was chromatographed on silica gel using 3% methanol/chloroformas eluant to yield 2.41 g (35%) of the desired product: ¹H-NMR isconsistent with structure; MS (ion spray) 608.3 (M+1); Anal. Calc'd forC₃₂H₄₁N₅O₇: C, 63.25; H, 6.80; N, 11.52. Found: C, 63.51; H, 6.79; N,11.74.

Example 173

To a solution of the product of Preparation 329, 2.2 g (3.6 mmol) in 25mL of dichloromethane was added 8 mL of trifluoroacetic acid. Thereaction mixture was stirred for 1 h, then concentrated. The residue waspartitioned between chloroform and saturated sodium carbonate and wasextracted with chloroform. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated. Theresidue was dissolved in ethyl acetate and a saturated solution ofhydrochloric acid in diethyl ether was added. The mixture wasconcentrated to yield 1.7 g (81%) of the desired isomer as a whitesolid: ¹H-NMR is consistent with structure; MS (ion spray) 508.3 (M+1);Anal. Calc'd for C₂₇H₃₁N₅O₅.2.3HCl: C, 55.00; H, 5.69; N, 11.89. Found:C, 55.06; H, 6.01; N, 11.41.

To a solution of the product of Preparation 327, 3.45 g (15.0 mmol) in100 mL of dichloromethane was added 3.0 g (18.0 mmol) of1,1′-carbonyldiimidazole. The reaction mixture was stirred overnight atambient temperature then 8.9 mL (75 mmol) of 4-methylpiperidine wasadded. The reaction mixture was stirred overnight at ambient temperaturethen concentrated. The residue was partitioned between ethyl acetate and0.1N aqueous hydrochloric acid and washed with 0.1N aqueous hydrochloricacid. The combined aqueous layers were extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was chromatographed onsilica gel using 80% ethyl acetate/hexanes as eluant to yield 4.4 g(85%) of the desired product as a yellow oil: ¹H-NMR is consistent withstructure; MS (ion spray) 359.2 (M+1); Anal. Calc'd forC₁₈H₂₂N₄O₄.0.3CHCl₃: C, 56.46; H, 5.78; N, 14.43. Found: C, 56.81; H,5.98; N, 14.42.

Reaction of the product of Preparation 330 (4.2 g, mmol), 10% palladiumon carbon (5.2 g), tetrahydrofuran (80 mL), the product of Preparation1d, (4.5 g, 11.7 mmol), 1-hydroxbenzotriazole (1.8 g, 12.9 mmol),dicyclohexylcarbodiimide (2.7 g, 12.9 mmol), as in described inPreparation 329 gave 2.2 g (27%) of the desired product as a tan foam:¹H-NMR is consistent with structure; MS (ion spray) 691.3 (M+1); Anal.Calc'd for C₃₇H₅₀N₆O₇: C, 64.33; H, 7.30; N, 12.17. Found: C, 64.04; H,7.41; N, 11.88.

Example 174

Reaction of the product of Preparation 331 (1.95 g, 2.8 mmol),trifluoroacetic acid (8 mL), dichloromethane (25 mL), as described inExample 173 gave 1.7 g (90%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (ion spray) 591.6 (M+1); Anal.Calc'd for C₃₂H₄₂N₆O₅.2.4HCl: C, 56.67; H, 6.60; N, 12.39. Found: C,56.94; H, 6.63; N, 12.04.

Example 175

To a solution of the product of Preparation 8, Examples, Part 1, 2.5 g(4.1 mmol) in 12 mL of dichloromethane was added 4 mL of trifluoroaceticacid. The solution was stirred for 2 h and was then concentrated. Theresidue was partitioned between ethyl acetate and saturated sodiumbicarbonate and was then extracted with ethyl acetate. The combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered and concentrated to yield 1.88 g (90%) of the desired productas a white foam: ¹H-NMR is consistent with structure; MS (ion spray)508.3 (M+1); Anal. Calc'd for C₂₇H₃₃N₅O₅.1H₂O: C, 61.70; H, 6.71; N,13.32. Found: C, 61.79; H, 6.25; N, 13.07.

Example 176

To a solution of the product of Example 175—438377, 1.66 g (3.3 mmol) in50 mL of methanol was added 0.6 g of lithium borohydride. The reactionmixture was stirred 10 min. then concentrated. The residue waspartitioned between ethyl acetate and water and was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The desired product wasrecrystallized from ethyl acetate/hexanes to yield 0.9 g (58%) of awhite solid: ¹H-NMR is consistent with structure; MS (ion spray) 466.3(M+1); Anal. Calc'd for C₂₅H₃₁N₅O₄.0.3H₂O: C, 63.76; H, 6.76; N, 14.87.Found: C, 63.87; H, 6.90; N, 14.77.

To a solution of the product of Preparation 8 from Examples Part 1, 3.0g (5.2 mmol), N-methylmorpholine, 0.63 mL (5.7 mmol) and4-dimethylaminopyridine, 20 mg in 30 mL of dichloromethane at 0° C. wasadded 0.55 mL (5.7 mmol)of ethyl chloroformate. After stirring at 0° C.for 1 h, the reaction mixture was concentrated to dryness. The residuewas partitioned between ethyl acetate and 1N HCl and was extracted withethyl acetate. The combined organics were washed with 1N HCl, brine,dried over sodium sulfate, filtered and concentrated to dryness. Thecrude material was chromatographed on silica gel using 3%methanol/chloroform as eluant to yield 2.7 g (85%) of the desiredproduct as a white foam: ¹H-NMR is consistent with structure; MS (ionspray) 608.1 (M+1); Anal. Calc'd for C₃₂H₄₁N₅O₇: C, 63.

Reaction of the product of Preparation 8 (0.4 g, 0.69 mmol),N-methylmorpholine (0.08 mL, 0.69 mmol), isobutyl chloroformate (0.1 mL,0.76 mmol) in dichloromethane (6 as described in Preparation 332, gave0.37 g (84%) of the desired product as a tan foam: ¹H-NMR is consistentwith structure; MS (FD) 635 (M+); Anal. Calc'd for C₃₄H₄₅N₅O₇: C, 64.23;H, 7.13; N, 11.02. Found: C, 64.15; H, 7.02; N, 10.94.

Example 177

Reaction of the product of Preparation 333 (0.31 g, 0.5 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL), as described inPreparation 175, gave 0.25 g (83%) of the desired product as a tansolid: ¹H-NMR is consistent with structure; MS (FD) 535 (M+).

Reaction of the product of Preparation 8 from Examples Part 1 (0.6 g,1.0 mmol), N-methylmorpholine (0.1 mL, 1.0 mmol), phenyl chloroformate(0.14 mL, 1.1 mmol), dichloromethane (6 mL), as described in Preparation332 gave 0.4 g (61%) of the desired mixture of isomers as a tan foam:¹H-NMR is consistent with structure; MS (FD) 655.3 (M+) ; Anal. Calc'dfor C₃₆H₄₁N₅O₇: C, 65.94; H, 6.30; N, 10.68. Found: C, 65.64; H, 6.42;N, 10.43.

Example 178

Reaction of the product of Preparation 334 (0.37 g, 0.56 mmol),triflouroacetic acid (2 mL), dichloromethane (6 mL), as in described inExample 175 gave 0.32 g (91%) of the desired product as a white solid:¹H-NMR is consistent with structure; MS (FD) 555 (M+); Anal. Calc'd forC₃₁H₃₃N₅O₅.2HCl: C, 59.24; H, 5.61; N, 11.14. Found: C, 59.30; H, 5.88;N, 10.97.

Reaction of the product of Preparation 8 from Examples Part 1 (0.4 g,0.69 mmol), N-methylmorpholine (0.08 mL, 0.69 mmol), benzylchloroformate (0.11 mL, 0.76 mmol), dichloromethane (6 mL), as describedin Preparation 332 gave 0.32 g (70%) of the desired product as a whitefoam: ¹H-NMR is consistent with structure; MS (FD) 669 (M+).

Example 179

Reaction of the product of Preparation 335 (0.27 g, 0.4 mmol),trifluoroacetic acid (2 mL), dichloromethane (6 mL),as described inPreparation 175, gave 0.24 g (92%) of the desired product as a tansolid: ¹H-NMR is consistent with structure; MS (FD) 569 (M+); Anal.Calc'd for C₃₂H₃₅N₅O₅.2HCl: C, 59.81; H, 5.80; N, 10.90. Found: C,60.05; H, 6.07; N, 10.66.

To a suspension of 60% sodium hydride in mineral oil (26.0 g , 0.6 mmol)stirring in dimethylformamide (500 mL) at −5° C. was slowly added4-nitroimidazole (73.5 g, 0.650 mol). After 30 min, ethyl bromoacetate(100 g, 0.599 mol) was added neat over 15 minutes via addition funnel.After 24 h, the solution was concentrated, diluted with ethyl acetatewashed with water. The organic extract was dried over sodium sulfate andconcentrated then triturated in ether to collect 67. 1 g (56%) of thedesired product as pale yellow needles: ¹H NMR consistent withstructure; MS FD+=199; Anal. Calcd. for C₇H₉N₃O₄: C, 42.21; H, 4.55; N,21.20. (Found) C, 43.90; H, 4.58; N, 22.02.

The product of Preparation 336 was reduced and coupled to give the esterwhich was then dissolved in methanol (400 ml) at room temp. 1 M lithiumhydroxide (45.2 ml, 45.3 mol) was added drop-wise over 10 minutes. After20 min, the mixture was concentrated then diluted with 150 mL 10% aceticacid/ethyl acetate and concentrated and extracted with ethyl acetate.The combined organic extracts were dried over sodium sulfate, andconcentrated to give 9.26 g (81%) of the desired material as a whiteamorphous powder: ¹H NMR consistent with structure; MS FD+=504; Anal.Calcd. For C₂₄H₃₃N₅O₇: C, 57.25; H, 6.61; N, 13.91. (Found) C, 57.04; H,6.83; N, 14.07.

To a solution of the product of Preparation 337 (250 mgs, 0.49 mmol) and1-hydroxybenzotriazole (67 mgs, 0.5 mmol) stirring in dry dioxane (5 mL)was added dicyclohexylcarbodiimide (107 mg, 0.521). After 15 min,piperidine(49 mg, 0.5 mmol) was added neat. After 18 h, the reactionmixture was filtered and concentrated. Purification by via radialchromatography (4 mm silica gel plate, 6% methanol/methylene chloride)gave 105 mg (36%) of a white amorphous foam: used in the next reactionwithout further purification.

Example 180

To a solution of the product of Preparation 338 (105 mg, 0.18mmol)stirring in dichloromethane (5 mL) at room temperature was addedanisole 0.2 mL) followed by trifluoroacetic acid (2 mL). After 2 h, thereaction mixture was concentrated and triturated with diethyl ether togive 86 mg (67%) of desired product as a white amorphous solid: ¹H NMRconsistent with structure; MS FD+=484; Anal. Calcd. for C₂₅H₃₆N₆O₄×2trifluoroacetic acid: C, 48.87; H, 5.38; N, 11.79. (Found) C, 48.71; H,5.30; N, 11.59.

Example 181

Reaction of the product of Preparation 337 (250 mg, 0.5 mmol) and3-methyl piperidine (49 mg, 0.5 mmol) as described in Preparation 338gave the corresponding amide which deprotected according to Example 180to provide the desired product as a white amorphous solid: ¹H NMRconsistent with structure; MS FD+=485; Anal. Calcd. for C₂₅H₃₆N₆O₄×2trifluoroacetic acid: C, 48.87; H, 5.38; N, 11.79. (Found) C, 48.61; H,5.25; N, 11.61.

Example 182

Reaction of the product of Preparation 337 (250 mg, 0.5 mmol) and2-methyl piperidine (49 mg, 0.5 mmol) as described in Preparation 338gave the corresponding amide which deprotected according to Example 180to provide the desired product as a white amorphous solid: ¹H NMRconsistent with structure; MS FD+=485; Anal. Calcd. for C₂₅H₃₆N₆O₄×2trifluoroacetic acid: C, 48.87; H, 5.38; N, 11.79. (Found) C, 48.65; H,5.39; N, 11.64.

Example 183

Reaction of the product of Preparation 337 (250 mg, 0.5 mmol) and2-methyl pyrrolidine (42 mg, 0.5 mmol) as described in Preparation 338gave the corresponding amide which deprotected according to Example 180to provide the desired product as a white amorphous solid: ¹H NMRconsistent with structure; MS FD+=470; Anal. Calcd. for C₂₄H₃₄N₆O₄×2trifluoroacetic acid: C, 48.14; H, 5.19; N, 12.03. (Found) C, 47.21; H,5.37; N, 11.73.

Example 184

Reaction of the product of Preparation 337 (250 mg, 0.5 mmol) and3-methyl pyrrolidine (42 mg, 0.5 mmol) as described in Preparation 338gave the corresponding amide which deprotected according to Example 180to provide the desired product as a white amorphous solid: ¹H NMRconsistent with structure; MS IS+=471; Anal. Calcd. for C₂₄H₃₄N₆O₄×2trifluoroacetic acid: C, 48.14; H, 5.19; N, 12.03. (Found) C, 48.02; H,5.11; N, 11.83.

Example 185

Reaction of the product of Preparation 337 (250 mg, 0.5 mmol) and4-propylpiperidine (63 mg, 0.5 mmol) as described in Preparation 338gave the corresponding amide which deprotected according to Example 180to provide the desired product as an off-white solid: ¹H NMR consistentwith structure; MS IS+=513; Anal. Calcd. for C₂₇H₄₀N₆O₄×2trifluoroacetic acid: C, 50.27; H, 5.72; N, 11.35. (Found) C, 52.30; H,6.37; N, 12.29.

Example 186

Reaction of the product of Preparation 337 (250 mg, 0.5 mmol) andpiperidine (49 mg, 0.5 mmol) as described in Preparation 338 gave thecorresponding amide which deprotected according to Example 180 toprovide the desired product as an off-white amorphous solid: ¹H NMRconsistent with structure; MS FD+=546; Anal. Calcd. for C₃₀H₃₈N₆O₄×2trifluoroacetic acid: C,48.14; H, 5.19; N, 12.03. (Found) C, 48.02; H,5.11; N, 11.83.

Example 187

Reaction of the product of Preparation 337 (1.75 g, 3.48 mmol),dicyclohexylcarbodiimide (717 mg, 3.48 mmol), 1-hydroxybenzotriazole(470 mg, 3.48 mmol), and pyrrolidine (0.29 mL, 3.48 mmol) as describedin Preparation 338 gave 870 mg (45%) of the corresponding amide whichwas deprotected according to Example 180 using anisole (1 mL) andtrifluoroacetic acid (10 mL) to yield 580 mg (54%) of final product as atan amorphous solid: ¹H NMR consistent with structure; MS IS+=457; Anal.Calcd. for C₂₃H₃₂N₆O₄×2 trifluoroacetic acid: C, 47.37; H, 5.01; N,12.28. (Found) C, 51.40; H, 5.81; N, 14.34.

Example 188

Reaction of the product of Preparation 337 (1.7 g, 3.38 mmol),dicyclohexylcarbodiimide (697 mg, 3.38 mmol), 1-hydroxybenzotriazole(456 mg, 3.38 mmol), 4-(p-fluorobenzoyl)piperidine hydrochloride (823mg, 3.38 mmol), and triethylamine (0.47 mL, 3.38 mmol) as described inPreparation 338 gave 1.96 g (84%) of the corresponding amide which wasdeprotected according to Example 180 using anisole (1 mL) andtrifluoroacetic acid (10 mL) to yield 1.28 g (55%) of final product asan off-white powder: ¹H NMR consistent with structure; MS IS+=593; Anal.Calcd. for C₃₁H₃₇FN₆O₅×2 trifluoroacetic acid: C, 51.22; H, 4.79; N,10.24. (Found) C, 52.71; H, 5.07; N, 10.92.

Example 189

Reaction of the product of Preparation 337 (400 mg, 0.79 mmol),dicyclohexylcarbodiimide (164 mg, 0.79 mmol), 1-hydroxybenzotriazole(107 mg, 0.79 mmol), and cyclohexylamine (78 mg, 0.79 mmol) as describedin Preparation 338 gave 234 mg (50%) of the corresponding amide whichwas deprotected according to Example 180 using anisole (0.05 mL) andtrifluoroacetic acid (4 mL) to yield 220 mg (77%) of final product as awhite amorphous solid: ¹H NMR consistent with structure; MS IS+=485;Anal. Calcd. for C₂₅H₃₆N₆O₄×2 trifluoroacetic acid: C, 48.88; H, 5.38;N, 11.79. (Found) C, 48.70; H, 5.52; N, 11.81.

Example 190

Reaction of the product of Preparation 337 (400 mg, 0.79 mmol),dicyclohexylcarbodiimide (164 mg, 0.79 mmol), 1-hydroxybenzotriazole(107 mg, 0.79 mmol), and 4-benzylpiperidine (139 mg, 0.79 mmol) asdescribed in Preparation 338 gave 196 mg (68%) of the correspondingamide which was deprotected according to Example 180 using anisole (0.05mL) and trifluoroacetic acid (4 mL) to yield 196 mg(68%) of finalproduct as a white amorphous solid: ¹H NMR consistent with structure; MSIS+=561; Anal. Calcd. for C₃₁H₄₀N₆O₄×2 trifluoroacetic acid: C, 52.37;H, 5.02; N, 10.47. (Found) C, 52.55; H, 5.33; N, 10.56.

Example 191

Reaction of the product of Preparation 337 (400 mg, 0.79 mmol),dicyclohexylcarbodiimide (164 mg, 0.79 mmol), 1-hydroxybenzotriazole(107 mg, 0.79 mmol), and 4-ethylpiperidine (89 mg, 0.79 mmol) asdescribed in Preparation 338 gave 236 mg (50%) of the correspondingamide which was deprotected according to Example 180 using anisole (0.05mL) and trifluoroacetic acid (4 mL) to yield 204 mg (71%) of finalproduct as a white amorphous solid: ¹H NMR consistent with structure; MSFD+=498; Anal. Calcd. for C₂₆H₃₈N₆O₄×2 trifluoroacetic acid: C, 49.59;H, 5.55; N, 11.57. (Found) C, 48.77; H, 5.29; N, 11.37.

Example 192

Reaction of the product of Preparation 337 (400 mg, 0.79 mmol),dicyclohexylcarbodiimide (164 mg, 0.79 mmol), 1-hydroxybenzotriazole(107 mg, 0.79 mmol), 4-benzoylpiperidine hydrochloride (179 mg, 0.79mmol), and triethylamine (0.11 mL, 0.79 mmol) as described inPreparation 338 gave 175 mg (33%) of the corresponding amide which wasdeprotected according to Example 180 using anisole (0.05 mL) andtrifluoroacetic acid (4 mL) to yield 170 mg (82%) of final product as awhite amorphous solid: ¹H NMR consistent with structure; MS IS+=575;Anal. Calcd. for C₃₁H₃₈N₆O₅×2 trifluoroacetic acid: C, 52.37; H, 4.99;N, 10.47. (Found) C, 52.13; H, 5.03; N, 10.62.

Example 193

Reaction of the product of Preparation 337(400 mg, 0.79 mmol),dicyclohexylcarbodiimide (164 mg, 0.79 mmol), 1-hydroxybenzotriazole(107 mg, 0.79 mmol), and 4-t-butylpiperidine (112 mg, 0.79 mmol) asdescribed in Preparation 338 gave 342 mg (69%) of the correspondingamide which was deprotected according to Example 180 using anisole (0.05mL) and trifluoroacetic acid (4 mL) to yield 287 mg (70%) of finalproduct as a white amorphous solid: ¹H NMR consistent with structure; MSIS+527; Anal. Calcd. for C₂₈H₄₂N₆O₄×2 trifluoroacetic acid: C, 50.93; H,5.84; N, 11.14. (Found) C, 50.65; H, 5.99; N, 11.28.

Example 194

Reaction of the product of Preparation 337 (400 mg, 0.79 mmol),dicyclohexylcarbodiimide (164 mg, 0.79 mmol), 1-hydroxybenzotriazole(107 mg, 0.79 mmol), and 4-isopropylpiperidine (101 mg, 0.79 mmol) ) asdescribed in Preparation 338 gave 208 mg (43%) of the correspondingamide which was deprotected according to Example 180 using anisole (0.05mL) and trifluoroacetic acid (4 mL) to yield 197 mg (78%) of finalproduct as a white amorphous solid: ¹H NMR consistent with structure; MSIS+=513; Anal. Calcd. for C₂₇H₄₀N₆O₄×2 trifluoroacetic acid: C, 50.27;H, 5.68; N, 11.35. (Found) C, 50.21; H, 5.78; N, 11.64.

To a solution of the product of Preparation 337 (400 mg, 0.79 mmol) andN-methyl morpholine (0.1 mL) stirring in dichloromethane (20 mL) at 0°C. was added isobutyl chloroformate (0.13 mL, 1 mmol). After 15 min,benzylamine (0.11 mL, 1 mmol) was added drop-wise and after 30 min thereaction mixture was quenched with water and washed with saturatedsodium bicarbonate solution, water, and 1N HCl. The organic extract wasthen dried over sodium sulfate, concentrated and then purified by flashchromatography (silica gel, 5% methanol/dichloromethane) to yield 199(42%) mg of the desired product as a yellow foam: ¹H NMR consistent withstructure; MS FD+=592; Anal. Calcd. for C₃₁H₄₀N₆O₆: C, 62.82; H, 6.80;N, 14.18. (Found) C, 61.82; H, 6.72; N, 13.75.

Example 195

To a solution of the product of Preparation 339 (183 mg, 0.31) stirringin dichloromethane (5 mL) at room temperature was added anisole (0.2 mL)followed by trifluoroacetic acid (2 mL). After 2 h, the reaction mixturewas concentrated and subsequently triturated with diethyl ether toprovide 93 mg (42%) of desired product as a white amorphous solid: 1HNMR consistent with structure; MS FD+=492; Anal. Calcd. forC₂₆H₃₂N₆O₄×2trifluoroacetic acid: C, 50.00; H, 4.76; N, 11.66. (Found)C, 50.28; H, 4.93; N, 11.59.

To a mixture of potassium t-butoxide (16.2 g, 145 mmol) stirring indimethylformamide (100 mL) was added 4-nitroimidazole (13.6 g, 120.7mmol) portion-wise over 30 min. After 1 h,ethyl-1-bromocyclobutanecarboxylate (25 g, 120.7 mmol) was slowly added.The mixture was heated to 100° C., and after 36 h, the mixture wascooled to room temperature and concentrated. The resulting solid wastriturated in diethyl ether and filtered. The filtrate was concentratedand purified by flash chromatography (silica gel; 60% ethylacetate/hexanes) to yield 3.86 g (13%) of the desired product as a clearyellow oil: ¹H NMR consistent with structure; MS FD+=239; Anal. Calcd.for C₁₀H₁₃N₃O₄: C, 50.21; H, 5.48; N, 17.56; (Found) C, 50.36; H, 5.60;N, 17.54.

To a solution of the product of Preparation 340 (3.6 g, mmol) in dioxane(50 mL) was added 5% palladium on carbon (0.9 g). The resulting mixturewas hydrogenated at room temperature at 40 p.s.i on a Parr apparatus for30 min.

This mixture was then filtered through celite and added to solution ofthe product of Preparation 1d (5.73 g, 15.05 mmol),1-hydroxybenzotriazole (2.03 g, 15.05 mmol), anddicyclohexylcarbodiimide (3.11 g, 15.05 mmol) in dioxane (75 mL). After18 h, the reaction was filtered and the filtrate concentrated. Theresulting orange foam was purified by flash chromatography (silica gel;methanol/dichloromethane) to yield 2.63 g of the desired product as ayellow foam: ¹H NMR consistent with structure; MS IS+=572.

To a solution of the product of Preparation 341 (2.6 g, 4.55 mmol)stirring in methanol (80 mL) at room temperature was slowly added 1MLiOH (9.1 mL, 9.1 mmol) drop-wise. After 90 min, the reaction mixturewas concentrated then diluted with 30 mL 10% acetic acid/ethyl acetateand concentrated. The resulting concentrate was diluted with 50 mL 10%acetic acid/ethyl acetate and washed with water. The organic extract wasdried over sodium sulfate and then concentrated. Triturate the solid indiethyl ether gave 620 mg (25%) of desired product as a white amorphouspowder: ¹H NMR consistent with structure; MS IS+=544.

To a solution of the product of Preparation 342 (600 mg, 1.10 mmol) and1-hydroxybenzotriazole (149 mg, 1.10 mmol)stirring in dioxane (10 mL) atroom temperature was added dicyclohexylcarbodiimide (228 mg, 1.10 mmol).After 15 min, 4-methylpiperidine (109 mg, 1.10 mmol) was added. After 18h, the mixture was filtered and the filtrate concentrated. The resultingmaterial was purified by radial chromatography to yield 200 mg (29%)ofthe desired product as a white amorphous foam: ¹H NMR consistent withstructure; MS IS+=625.

Example 196

To a solution of the product of Preparation 343 (200 mg, 0.32 mmol)stirring in dichloromethane (5 mL) at room temperature was added anisole(0.05 mL) followed by trifluoroacetic acid (2 mL). After 2 h, thereaction mixture was concentrated then triturate in diethyl ether toprovide 118 mg (49%) of desired product as a white amorphous solid: ¹HNMR consistent with structure; MS IS+=525; Anal. Calcd. forC₂₈H₄₀N₆O₄×2trifluoroacetic acid: C, 51.06; H, 5.62; N, 11.16. (Found)C, 53.40; H, 6.06; N, 11.99.

To a solution of the product of Preparation 5 (10.0 g, 16.4 mmol)stirring in tetrahydrofuran (150 mL) at room temperature was added1-hydroxybenzotriazole (2.22 g, 16.4 mmol) and1,3-dicyclohexylcarbodiimide (3.38 g, 16.4 mmol). After 15 min,pyrrolidine (1.37 mL, 16.4 mmol) was added. After 16 h, the reactionmixture was filtered and concentrated. The resulting crude material waspurified by flash chromatography (silica gel, 5%methanol/dichloromethane) to yield 7.05 g (65%) of the desired productas a yellow foam: ¹H-NMR consistent with product; MS (ion spray) 663(M+1); Anal. Calcd for C₃₅H₄₆N₆O₇: C, 63.43; H, 7.00; N, 12.68. (Found)C, 62.69; H, 6.87; N, 12.91.

Examples 197 and 198

To the product of Preparation 344 (7.0 g, 10.6 mmol) was added asaturated solution of HCl (g)/acetic acid (100 mL). After 4 h, thereaction mixture was concentrated then partitioned between ethyl acetateand saturated sodium bicarbonate. The organic layer was removed, driedover sodium sulfate and concentrated to yield 5.59 g (94%) of the freebase as a light yellow foam. The diastereomeric material (3.45 g) waschromatographed on an 8×15 cm Prochrom column packed with KromsilCHI-DIMETHYLFORMAMIDE chiral phase using an eluent mixture of 3A alcoholand dimethylethylamine in heptane to provide the individualdiastereomers in pure form: ¹H NMR consistent with product; MS (ionspray) 563 (M+1); Anal. Calcd. for C₃₀H₃₈N₆O₅: C, 64.04; H, 6.81; N,14.94. (Found) C, 63.98; H, 6.82; N, 14.87.

Example 197. (Isomer 1) To a solution of the purified isomer in ethylacetate was added a saturated solution of hydrochloric acid in ethylacetate. The resulting slurry was concentrated to dryness to yield 1.50g (39%) of the desired product as an off-white solid: ¹H NMR consistentwith product; MS (ion spray) 563 (M+1); Anal. Calcd. for C₃₀H₃₈N₆O₅×2HCl: C, 56.69; H, 6.34; N, 13.22. (Found) C, 55.81; H, 6.40; N, 12.68.

Example 198. (Isomer 2) To a solution of the purified isomer in ethylacetate was added a saturated solution of hydrochloric acid in ethylacetate. The resulting slurry was concentrated to dryness to yield 1.43g (38%) of the desired product as an off-white solid: ¹H NMR consistentwith structure; MS (ion spray) 563 (M+1); Anal. Calcd. for C₃₀H₃₈N₆O₅×2HCl: C, 56.69; H, 6.34; N, 13.22. (Found) C, 55.71; H, 6.38; N, 12.74.

To a mixture of the product of Preparation 99 (6.0 g, 17.1 mmol) and 10%palladium on carbon (6.0 g) in tetrahydrofuran (100 mL). The reactionmixture was placed under a hydrogen atmosphere (40 psi) using a Parrapparatus for 30 min then filtered through Celite. The resultingsolution was then added to a previously prepared mixture of the productof Preparation 1L (6.66 g, 17.1 mmol), 1-hydroxybenzotriazole (2.31 g,17.1 mmol), and 1,3 dicyclohexylcarbodiimide (3.53 g, 17.1 mmol) intetrahydrofuran (75 mL). After 16 h at room temperature, the reactionmixture was concentrated and the crude material purified by flashchromatography (silica gel, 4% methanol/dichloromethane) to yield 6.17 g(52%) of the desired product as a brown foam: ¹H NMR consistent withstructure; MS (ion spray) 693 (M+1).

To a solution of the product Preparation 345 (4.6 g, 6.64 mmol) stirringin tetrahydrofuran (100 mL) at room temperature was added a solution oflithium hydroxide in water (40 mL of 1M). After 30 min, the reactionmixture was acidified with 5N HCl (8.5 mL). The resulting mixturediluted with water and exttraced with ethyl acetate. The combinedorganic extracts were dried over sodium sulfate and concentrated toyield 4.4 g (99%) of the desired product as a yellow foam.

To a solution of the product Preparation 346 (4.0 g, 6.02 mmol) stirringin tetrahydrofuran (50 mL) at room temperature was added1-hydroxybenzotriazole (813 mg, 6.02 mmol) and 1,3dicyclohexylcarbodiimide (1.24 g, 6.02 mmol). After 15 min,dimethylamine (3.0 mL of a 2M soln in tetrahydrofuran, 6.02 mmol) wasadded. After stirring for 16 h in a sealed flask, the reaction mixturewas filtered and concentrated. The resulting crude material was purifiedby flash chromatography (silica gel, 5% methanol/dichloromethane) toyield 2.79 g (68%) of the desired product as a yellow foam.

Examples 199 and 200

To the product of Preparation 347 (3.4 g, 5.0 mmol) was added asaturated solution of HCl(g)/acetic acid (50 mL). After 1.5 h, thereaction mixture was concentrated then partitioned between ethyl acetateand saturated sodium bicarbonate. The organic layer was removed, driedover sodium sulfate and concentrated to yield 2.45 g (84%) of the freebase as a light yellow foam. The diastereomeric material (2.45 g) waschromatographed on an 8×15 cm Prochrom column packed with Kromsil CHIchiral phase using an eluent mixture of 3A alcohol anddimethylethylamine in heptane to provide the individual diastereomers inpure form: ¹H NMR consistent with product; MS (ion spray) 592 (M+1);Anal. Calcd. for C₃₄H₃₇N₇O₃: C, 69.02; H, 6.30; N, 16.57. (Found) C,67.93; H, 6.29; N, 15.80.

Example 199. (Isomer 1) To a solution of the purified isomer in ethylacetate was added a saturated solution of hydrochloric acid in ethylacetate. The resulting slurry was concentrated to dryness to yield 992mg (37%) of the desired product as an off-white solid: ¹H NMR consistentwith product; MS (ion spray) 592 (M+1); Anal. Calcd. for C₃₄H₃₇N₇O₃×2HCl: C, 61.44; H, 5.91; N, 14.75. (Found) C, 59.54; H, 5.92; N, 13.76.

Example 200. (Isomer 2) To a solution of the purified isomer in ethylacetate was added a saturated solution of hydrochloric acid in ethylacetate. The resulting slurry was concentrated to dryness to yield 1.17g (40%) of the desired product as an off-white solid: ¹H NMR consistentwith structure; MS (ion spray) 592 (M+1); Anal. Calcd. for C₃₄H₃₇N₇O₃×2HCl: C, 61.44; H, 5.91; N, 14.75. (Found) C, 59.03; H, 6.04; N, 13.84.

To a suspension of sodium hydride (1.8 g of a 60 % dispersion in mineraloil, 45 mmol) stirring at 0° C. in diemthylformamide (50 mL) was slowlyadded 4-nitroimidazole (5.0 g, 44.2 mmol). After 1 h, a solution of4-fluorobenzyl bromide (5.5 mL, 44.2 mmol) in dimethylformamide (10 mL)was added dropwise over 10 min. After 16 h, the reaction mixture waswarmed to room temperature and concentrated. The resultant crudematerial was then diluted with hot methanol, filtered, allowed to cool,then filtered to yield 5.0 g (51%) of pale yellow crystals: ¹H NMRconsistent with structure; MS (ion spray) 222 (M+1); Anal. Calcd. forC₁₀H₈FN₃O₂: C, 54.31; H, 3.65; N, 19.00. Found: C, 53.81; H, 3.92; N,17.48.

To a slurry of Raney Nickel (116 mg) in dioxane (15 mL) was added aslurry of the product of Preparation 348 (582 mg, 2.63 mmol) in dioxane(20 mL). The reaction mixture was placed under a hydrogen atmosphere (60psi) using a Parr apparatus. After 30 min, the solution was filteredthrough Celite and the filtrate immediately added to a previouslyprepared mixture of the product of Preparation 1d (1.0 g, 2.63 mmol),1-hydroxybenzotriazole (355 mg, 2.63 mmol), and 1,3dicyclohexylcarbodiimide (543 mg, 2.63 mmol) in dioxane (25 mL). After16 h, the reaction mixture was concentrated and the crude materialpurified by flash chromatography (silica gel, 5%methanol/dichloromethane) to give the desired product. This material wasthen crystallized from diethyl ether to yield 150 mg (10%) of thedesired product as a white powder: ¹H NMR consistent with structure.

Example 201

To the product of Preparation 349 (150 mg, 0.27 mmol) stirring indichloromethane (5 mL) at room temperature was added anisole (0.05 mL)and trifluoroacetic acid (2 mL). After 3 h, the mixture wasconcentrated, triturated extensively in diethyl ether, and the productcollected via filtration to provide 101 mg (55%) of desired product as awhite powder: ¹H NMR consistent with structure; MS (ion spray) 454(M+1); Anal. Calcd. For C₂₄H₂₈FN₅0₃×2TFA: C, 49.34; H, 4.44; N, 10.28.Found: C, 49.64; H, 4.58; N, 10.36.

To a suspension of sodium hydride (1.56 g of a 60 % dispersion inmineral oil, 39 mmol) stirring in DIMETHYLFORMAMIDE (50 mL) at 0° C. wasslowly added 4-nitroimidazole (4.0 g, 35.4 mmol). After 1 h, a solutionof 4-trifluoro-methoxybenzyl bromide 9.03 g, 35.4 mmol) indimethylformamide (10 mL) was added dropwise over 10 min. After 16 h,the reaction mixture was warmed to room temperature then concentrated.The resultant crude material was then purified by flashchromatography(silica gel, 100% dichloromethane) and the productsubsequently crystallized from diethyl ether to yield 3.95 g (39%) ofdesired product as white needles: ¹H NMR consistent with structure; MS(ion spray) 288 (M+1); Anal. Calcd. for C₁₁H₈F₃N₃O₃: C, 45.99; H, 2.79;N, 14.63; F, 19.86. (Found) C, 46.27; H, 2.86; N, 14.86; F, 19.74.

To a slurry of Raney Nickel (150 mg) in dioxane (15 mL) was added aslurry of the product of Preparation 350 (755 mg, 2.63 mmol) in dioxane(20 mL). The reaction mixture was placed under a hydrogen atmosphere (60psi) using a Parr apparatus. After 30 min, the solution was filteredthrough Celite and the filtrate immediately added to a previouslyprepared mixture of the product of Preparation 1d (1.0 g, 2.63 mmol),1-hydroxybenzotriazole (355 mg, 2.63 mmol), and 1,3dicyclohexylcarbodiimide (543 mg, 2.63 mmol) in dioxane (25 mL). After16 h, the reaction mixture was concentrated and the crude materialpurified by flash chromatography (silica gel, 5%methanol/dichloromethane) to provide 171 mg (10%)of the desired productas a white foam: ¹H NMR consistent with structure; used without furthercharacterization.

Example 202

To the product of Preparation 351 (171 mg, 0.28 mmol) stirring indichloromethane (5 mL) at room temperature was added anisole (0.05 mL)and trifluoroacetic acid (2 mL). After 3 h, the mixture wasconcentrated, triturated extensively in diethyl ether, and the productcollected via filtration to provide 84 mg (40%) of desired product as awhite powder: ¹H NMR consistent with structure; MS (ion spray) 520(M+1); Anal. Calcd. For C₂₅H₂₈F₃N₅O₄×2 TFA: C, 46.59; H, 4.04; N, 9.37.Found: C, 48.48; H, 4.48; N, 10.04.

A cold (0-5° C.) solution of 5.0 g (24.37 mmol) of Boc-D-serine in 20 mLof dry N,N-dimethylformamide was added to a stirred suspension of sodiumhydride (60% dispersion in mineral oil, 2.2 g, 55 mmol) in 60 mL of drydimethylformamide at 0-5° C. under nitrogen over 5 min. The resultinglight yellow brown suspension was stirred at 0-5° C. until gasevaluation nearly ceased (˜15 min). Then a cold (0-5° C.) solution of4-fluorobenzyl bromide (3.12 mL, 25 mmol) in 10 mL of dryN,N-dimethylformamide (Additional 10 mL of dimethylformamide was used aswashings) was added to the stirred mixture over 5 min. The resulting offwhite suspension was stirred at 0-5° C. for 2 h, during which time themixture turned to a thick suspension and the magnetic stirring becameineffective. The reaction flask was shaken by hand several times. Thecooling bath was removed and the mixture was allowed to warm to roomtemperature while shaking the reaction flask occasionally by hand. Bythe time the mixture reached the room temperature, the suspensionthinned and the magnetic stirring became effective. The mixture wasstirred at ambient temperature for additional 1 h (total 5 hours). Themixture was concentrated and the oily residue was dissolved in 150 mL ofwater and extracted with ether. The aqueous layer was cooled to 0-5° C.,acidified to pH ˜3 with cold (0-5° C.) 0.5N HCl, and quickly extractedwith ethyl acetate. The aqueous layer was saturated with sodium chlorideand extracted with ethyl acetate. The ethyl acetate extracts werecombined, washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated to dryness to give 6.86 g (89.9%) of thedesired product as a light yellow viscous oil which was used in the nextstep without further purification: ¹H-NMR (δ, DMSO)1.38 (s, 9H),3.60-3.70 (m, 2H), 4.15-4.25 (m, 1H), 4.45 (s, 2H), 6.97 (d, J=8.3 Hz,1H ), 7.16 (t, J=8.7 Hz and 9.0 Hz, 2H), 7.30-7.40 (m, 2H), 12.65 (br s,1H); MS (ion spray) 314 (M+1).

Trifluoroacetic acid (40 mL) was added to a stirred solution of 6.5 g(20.75 mmol) of the product of Preparation 352 in 40 mL ofdichloromethane and the mixture was stirred at ambient temperature for 1h, then it was concentrated to dryness. The resulting oily residue wasdissolved in 30 mL of deionized water, cooled in ice-water bath,neutralized to pH ˜7, and the separated white precipitate was filtered.The precipitate was washed with ether (5×10 mL) to remove the yellowbrown impurity and the resulting white precipitate was dried to aconstant weight to give 2.45 g (55.4%) of the desired product as a whitepowder: ¹H-NMR (δ, DMSO)3.37 (dd, J=3.4, 7.9 Hz, 1H), 3.60 (dd, J=7.9Hz, 1H), 3.77 (dd, J=3.4 Hz, 1H), 4.47 (s, 2H), 7.15-7.25 (m, 2H),7.35-7.48 (m, 2H), 7.65 (br s, 1H); MS (ion spray) 214 (M+1); Anal.Calc'd for C₁₀H₁₂FNO₃: C, 56.33; H, 5.67; N, 6.57. Found: C, 56.32; H,5.66; N, 6.39.

A solution of 1,3-dicyclohexylcarbodiimide (6.18 g, 30 mmol) in 30 mL oftetrahydrofuran was added to a stirred solution of 6.1 g (30 mmol) ofBoc-a-methylalanine and 4.14 g (36 mmol) of N-hydroxysuccinimide in 60mL of tetrahydrofuran at ambient temperature under nitrogen and themixture was stirred at ambient temperature under nitrogen for overnight.The mixture was cooled to ˜0° C. and filtered through celite. Theprecipitate was washed with cold (0-5° C.) tetrahydrofuran. The filtratewas concentrated to dryness and purified by flash chromatography (5%acetone/dichloromethane) to give 7.25 g (80.6%)of the desired product asa white powder: ¹H-NMR (δ, DMSO) 1.39 (s, 9H), 1.48 (s, 6H), 2.78 (s,4H), 7.57 (br s, ˜0.5H); MS (ion spray) 301 (M+1); Anal. Calc'd forC₁₃H₂₀FN₂O₆: C, 51.99; H, 6.71; N, 9.33. Found: C, 52.70; H, 6.67; N,9.30.

Forty mL of tetrahydrofuran was added to a stirred suspension of 4.26 g(20 mmol) of the product of Preparation 353 in 100 mL 1N sodiumbicarbonate and the mixture was stirred for 15 min to give a finesuspension. Forty mL of water was added to the reaction mixture todissolve the suspension to form a clear solution. To this stirredsolution at ambient temperature under nitrogen atmosphere was added asolution of 5.71 g (19 mmol) of the product of Preparation 354 in 60 mLof tetrahydrofuran over 3 h and the resulting mixture was stirred atambient temperature under nitrogen for 4 h. The resulting turbidsolution was diluted with 150 mL of water to form a clear solution whichwas extracted with petroleum ether (2×200 mL). The aqueous layer wascooled to 0-5° C., acidified to pH ˜3.0 with cold (0-5° C.) 1N HCl (˜100mL) followed by 0.5N HCl (˜15 mL)+, and the separated white precipitatewas quickly extracted with ethyl acetate (1×200 mL). The aqueous layerwas saturated with sodium chloride, further acidified to pH ˜1, andquickly extracted with ethyl acetate (1×200 mL). The ethyl acetateextracts were combined, washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated to dryness to give 7.03 g (92.9%) ofthe desired product as a white foam:¹H-NMR (δ, DMSO) 1.29 (s, 6H), 1.33(s, 9H), 3.66 (dd, J=4.0 Hz, 1H), 3.75 (dd, J=4.3 Hz, 1H), 4.38-4.48 (m,1H), 4.44 (s, 2H), 7.00-7.20 (m, 3H), 7.28-7.42 (m, 3H), 12.8 (br s,˜0.5H); MS (ion spray) 399 (M+1); Anal. Calc'd for C₁₉H₂₇FN₂O₆: C,57.28; H, 6.83; N, 7.03. Found: C, 57.05; H, 6.84; N, 6.87.

7.0 g of 5% palladium on carbon (dry) was added under nitrogenatmosphere to a solution of 6.7 g (22 mmol) of the product ofPreparation 3 from Examples Part 1 in 35 mL of tetrahydrofuran and theresulting slurry was hydrogenated at ˜50 psi of hydrogen for 2 h. Themixture was filtered through celite and the catalyst was washed withtetrahydrofuran (15×25 mL). The resulting yellow brown filtrate (˜300mL) was added to a mixture of 6.6 g (16.57 mmol) of the product ofPreparation 355 and 2.97 g (22 mmol) of 1-hydroxybenzotriazole. To thisstirred brown solution was added 3.7 g (18 mmol) of1,3-dicyclohexylcarbodiimide as solid in one lot and the mixture wasstirred at ambient temperature for 20 h, then it was concentrated. Theresidue was dissolved in 150 mL of ethyl acetate and filtered throughcelite. The brown filtrate was washed with 1N sodium bicarbonate, brine,dried over anhydrous sodium sulfate, filtered, and concentrated todryness to give 12.3 g of crude product as a tan foam which was purifiedby flash chromatography (silica gel, 3% methanol in dichloromethane) togive 7.75 g (71.3%) of the desired product as a tan foam: ¹H-NMR (δ,DMSO) 1.17 (t, J=7.2 Hz, 3H), 1.25-1.35 (m, 15H), 3.52-3.65 (m, 1H),3.66-3.72 (m, 1H), 3.76 (s, 3H), 4.21 (q, J=7.2, 2H), 4.42 (d, J=3.4 Hz,2H), 4.53-4.62 (m, 1H), 6.35 (d, J=3.4 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H),7.05-7.30 (m, 5H), 7.32 (d, J=8.7 Hz), 7.51 (s, 1H), 10.20 (br s, 1H);MS (ion spray) 656 (M+1); Anal. Calc'd for C₃₃H₄₂FN₅O₈: C, 60.45; H,6.46; N, 10.68. Found: C, 61.35; H, 6.57; N, 10.98.

14 mL (14 mmol) of 1M solution of lithium hydroxide was added in one lotto a stirred solution of the product of Preparation 356 (7.2 g, 11 mmol)in 51 mL of dioxane and 30 mL of deionized water. The mixture wasstirred at ambient temperature for 20 min and extracted it with ether(3×40 mL). The light yellow colored ether extracts were discarded. Thebrown aqueous layer (pH ˜12) was cooled in ice-water bath and acidifiedto pH ˜4 with cold 0.5N HCl and quickly extracted the separated lightbrown precipitate with ethyl acetate (1×150 mL). The light yellowcolored aqueous layer was saturated with sodium chloride, furtheracidified to pH ˜3 and extracted with ethyl acetate. The aqueous layerwas discarded. The organic extracts were combined, washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated todryness to give 6.9 g (100%) of the desired product as a tan foam:¹H-NMR (δ, DMSO) 1.20-1.45 (m. 15H), 3.50-3.60 (m, 1H), 3.65-3.72 (m,1H), 3.76 (s, 3H), 4.425 (d, J=3 Hz, 2H), 4.50-4.65 (m, 1H), 6.205 (d,1.9 Hz, 1H), 6.99 (d, J=8.7 Hz, 2H), 7.05-7.32 (m, 5H), 7.33 (d, J=8.7Hz, 2H), 7.51 (t, J=1.9 Hz, 1H), 10.20 (br s, 1H), 13.48 (br s, 1H); MS(ion spray) 628 (M+1), 629 (M+2); Anal. Calc'd for C₃₁H₃₈FN₅O₈ 0.5 H₂O:C, 58.31; H, 6.33; N, 10.99. Found: C, 58.75; H, 6.26; N, 10.56.

To a solution of 7.0 g (11 mmol) of the product of Preparation 357 in130 mL of N,N-dimethylformamide was added 1.42 mL (12 mmol) of4-methylpiperidine, 1.62 g (12 mmol) of 1-hydroxybenzotriazole hydrate,and 2.37 g (11.5 mmol) of dicyclohexylcarbodiimide. The reaction mixturewas stirred at ambient temperature for 38 h, then filtered, theprecipitate was washed with ethyl acetate (2×20 mL) and the filtrate wasconcentrated on rotavap. The resulting brown syrup was partitionedbetween ethyl acetate (200 mL) and 0.5N HCl (100 mL) and the layers werequickly separated. The organic extract was washed with 100 mL each ofsaturated sodium bicarbonate and brine. The organic extract was driedover anhydrous sodium sulfate, filtered, and concentrated to give 7 g ofcrude product as a tan foam which was purified by flash chromatography(silica gel, 3% methanol/dichloromethane) to give 5.7 g (73%) of thedesired product as light brown foam: ¹H-NMR (δ, DMSO) 0.12-0.30 (m, 0.5H), 0.75 (d, J=6.4 Hz, 1.5 H), 0.88 (d, J=6.0 Hz, 1.5 H), 0.80-1.15 (m,2H), 1.20-1.40 (m, 15 H), 1.45-1.67 (m, 2.5 H), 2.55-2.75 (m, 1.5 H),2.93-3.07 (m, 0.5 H), 3.50-3.60 (m, 1H), 3.60-3.70 (m, 1H), 3.75 (d,J=3.4 Hz, 3H), 3.60-3.85 (m, 1H), 4.30-4.45 (m, 1H), 4.425 (d, J=3.0 Hz,2H), 4.50-4.65 (m, 1H), 6.62 (d, J=12 Hz, 1H), 6.98 (t, J=9.4 Hz, 2H),7.05-7.45 (m, 10H), 10.13 (br s, 1H); MS (ion spray) 709 (M+1); Anal.Calc'd for C₃₇H₄₉FN₆O₇: C, 62.70; H, 6.97; N, 11.86. Found: C, 62.44; H,6.99; N, 11.89.

Examples 203 and 204

Trifluoroacetic acid (6 mL) was added to a solution of the product ofPreparation 358 (3.88 g, 5.47 mmol) in 15 mL of dichioromethane and theresulting brown solution was stirred at ambient temperature for 4 h. Themixture was poured into 300 mL of saturated sodium bicarbonate andextracted with ethyl acetate (1×150 mL). The yellow brown color organiclayer was separated and the aqueous layer was saturated with sodiumchloride and extracted with fresh ethyl acetate. The aqueous layer wasdiscarded. The organic extracts were combined, washed with brine, driedover anhydrous sodium sulfate, filtered, and concentrated to give 3.2 g(96%) of diastereomeric mixture of the desired product as a light brownfoam: ¹H-NMR (δ, DMSO) consistent with the structure; MS (ion spray) 609(M+1); Anal. Calc'd for C₃₂H₄₁FN₆O₅0.5 H₂O: C, 62.22; H, 6.85; N, 13.60.Found: C, 62.14; H, 6.62; N, 13.62. This material (3.0 g) was purifiedby HPLC (8×15 cm Prochrom column packed with Kromsil CHI-DMP chiralphase, eluted with a mixture of 3A alcohol and dimethylethylamine inheptane) to provide the individual diastereomers which were converted totheir respective hydrochloride salts as described below:

Example 203. (Isomer 1) 1.28 g (2.1 mmol) of pure free amine of isomer 1(lot # CJ4-LFK-53B) was dissolved in 21 mL of 1N HCl, diluted with 21 mLof deionized water, and the resulting solution was freeze-dried to give1.3 g (96%) of the desired product as a light brown powder: ¹H-NMR (δ,DMSO) 0.1-0.25 (m, 0.5 H), 0.75 (d, J=6.4 Hz, 1.5 H), 0.88 (d, J=6.0 Hz,1.5 H), 0.8-1.22 (m, 1.5 H), 1.22-1.40 (m, 0.5 H), 1.40-1.75 (m, 8.5 H),2.55-2.75 (m, 1.5 H), 2.95-3.10 (m, 0.5 H), 3.60-3.75 (m, 3H), 3.76 (d,J=3.4 Hz, 3H), 4.25-4.45 (m, 1H), 4.50 (s, 2H), 4.65-4.75 (m, 1H), 6.79(d, J=12.8 Hz, 1H), 6.95-7.45 (m, 9H), 7.80-7.95 (m, 1H), 8.19 (br s,3H, exchangeable with deuterium), 8.52 (d, J=6.8 Hz, 1H, exchangeablewith deuterium), 10.86 (br s, 1H, exchangeable with deuterium);t_(R)=7.40 min; MS (ion spray) 610 (M+1); Anal. Calc'd for C₃₂H₄₁FN₆O₅ 2HCl 0.5 H₂O: C, 55.73; H, 6.43; N, 12.19. Found: C, 55.50; H, 6.33; N,12.12.

Example 204. (Isomer 2) 1.1 g (1.8 mmol) of pure free amine of isomer 2(lot # CJ4-LFK-53A) was dissolved in 20 mL of 1N HCl, diluted with 20 mLof deionized water, and the resulting solution was freeze-dried to give1.1 g (95%) of the desired product as a light brown powder: ¹H-NMR (δ,DMSO) 0.05-0.25 (m, 0.5 H), 0.75 (d, J=6.4 Hz, 1.5 H), 0.89 (d, J=6.0Hz, 1.5 H), 0.8-1.40 (m, 2H), 1.40-1.70 (m, 8.5 H), 2.55-2.75 (m, 1.5H), 2.95-3.10 (m, 0.5 H), 3.60-3.75 (m, 3H), 3.77 (d, J=3.0 Hz, 3H),4.30-4.45 (m, 1H), 4.49 (s, 2H), 4.68-4.78 (m, 1H), 6.87 (d, J=13.6 Hz,1H), 6.98-7.18 (m, 4H), 7.25-7.45 (m, 5H), 8.05-8.20 (m, 1H), 8.27 (brs, 3H, exchangeable with deuterium), 8.57 (d, J=6.8 Hz, 1H, exchangeablewith deuterium), 11.04 (br s, 1H, exchangeable with deuterium);t_(R)=9.43 min; MS (ion spray) 610 (M+1); Anal. Calc'd for C₃₂H₄₁FN₆O₅ 2HCl 0.5 H₂O: C, 55.73; H, 6.43; N, 12.19. Found: C, 55.33; H, 6.40; N,12.02.

Preparation 359

This is Preparation 457 from Examples Part 2C.

5.5 g of 5% palladium on carbon was added under nitrogen atmosphere to asolution of 4.49 g (18 mmol) 4-nitropyrazole in 30 mL of tetrahydrofuranand the resulting slurry was hydrogenated at ˜50 psi of hydrogen for 2h. The mixture was filtered through celite and the catalyst was washedwith tetrahydrofuran (10×25 mL). The resulting yellow brown filtrate(˜300 mL) was added to a mixture of 6.05 g (16 mmol) of the product ofPreparation 1j and 2.43 g (18 mmol) of 1-hydroxybenzotriazole. To thisstirred brown solution was added 3.5 g (17 mmol) of1,3-dicyclohexylcarbodiimide and the mixture was stirred at ambienttemperature for 21 h, then concentrated. The residue was dissolved in150 mL of ethyl acetate and filtered through celite. The brown filtratewas washed successively with 100 mL each of 0.5N HCl, 1N sodiumbicarbonate, brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give 11.6 g of crude product as a tan foamwhich was purified by flash chromatography (silica gel, 3% methanol indichloromethane) to give 9.8 g (96%) of the desired product as a tanfoam; ¹H-NMR (δ, DMSO) 1.15 (t, J=7.1, 6.8 Hz, 3H), 1.20-1.40 (m, 15H),1.45-1.90 (m, 4H), 2.45-2.65 (m, 2H), 3.77 (s, 3H), 4.10-4.28 (m, 3H),6.30 (s, 1H), 6.98 (d, J=9.0 Hz, 2H), 7.10-7.30 (m, 6H), 7.36 (d, J=8.7Hz, 2H), 7.54 (d, J=5.3 Hz, 1H), 7.69 (d, J=0.75 Hz, 1H), 7.82 (be s,1H), 9.70 (br s, 1H); MS (ion spray) 636 (M+1); Anal. Calc'd forC₃₄H₄₅N₅O₇: C, 64.23; H, 7.13; N, 11.02. Found: C, 64.50; H, 7.25; N,11.06.

16.5 mL (16.5 mmol) of 1M solution of lithium hydroxide was added in onelot to a stirred solution of the product of Preparation 360 (8.3 g, 13mmol) in 60 mL of dioxane and 35 mL of deionized water. The mixture wasstirred at ambient temperature for 20 min and extracted it with ether(3×40 mL). The light yellow colored ether extracts were discarded. Thebrown aqueous layer (pH ˜12) was cooled in ice-water bath and acidifiedto pH ˜4 with cold 0.5N HCl and quickly extracted the separated lightbrown precipitate with ethyl acetate (1×200 mL). The light yellowcolored aqueous layer was saturated with sodium chloride, furtheracidified to pH ˜1-2 and extracted with ethyl acetate. The aqueous layerwas discarded. The organic extracts were combined, washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated todryness to give 7.9 g (100%) the desired product as a tan foam: ¹H-NMR(δ, DMSO/D₂O) 1.25-1.35 (m, 15H), 1.40-1.85 (m, 4H), 2.45-2.60 (m, 2H),3.75 (s, 3H), 4.12-4.27 (m, 1H), 6.14 (s, 1H), 6.97 (d, J=8.7 Hz, 2H),7.10-7.18 (m, 3H), 7.20-7.30 (m, 2H), 7.35 (d, J=8.7 Hz, 2H), 7.53 (d, i=6.4 Hz, 1H), 7.67 (d, J=3.0 Hz, 1H), 7.80 (br s, 1H, exchangeable withdeuterium), 9.70 (br s, 1H, exchangeable with deuterium), 13.30 (br S,1H, exchangeable with deuterium); MS (ion spray) 608 (M+1); Anal. Calc'dfor C₃₂H₄₁N₅O₇: C, 63.25; H, 6.80; N, 11.52. Found: C, 63.18; H, 6.98;N, 10,64.

To a solution of 6.08 g (10 mmol) of the product of Preparation 361 in100 mL of N,N-dimethylformamide was added 1.25 mL(15 mmol) ofpyrrolidine, 1.62 g (12 mmol) of 1-hydroxybenzotriazole hydrate, and2.27 g (11 mmol) of dicyclohexylcarbodiimide. The reaction mixture wasstirred at ambient temperature for 46 h, then concentrated. Theresulting brown syrup was dissolved in ethyl acetate (150 mL) andfiltered. The filtrate was washed successively with 0.5N HCl (2×25 mL),saturated sodium bicarbonate (2×25 mL) and brine (1×30 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give 5.96 g of crude product as a off whitefoam which was purified by flash chromatography (silica gel, 3%methanol/dichloromethane) to give 5.7 g (80.6%) of the desired productas white foam: ¹H-NMR (δ, DMSO) 1.20-1.40 (m, 15H), 1.45-1.95 (m, 8H),2.45-2.60 (m, 2H), 2.98-3.10 (m, 1H), 3.25-3.43 (m, 2H), 3.45-3.60 (m,1H), 3.76 (s, 3H), 4.15-4.30 (m, 1H), 6.36 (s, 1H), 6.98 (d, J=8.7 Hz,2H), 7.10-7.30 (m, 6H, 1H exchangeable with deuterium), 7.34 (dd, J=8.7,1.9 Hz, 2H), 7.50 (d, J=10.6 Hz, 1H), 7.63 (d, J=6.4 Hz, 1H), 7.70-7.90(m, 1H, exchangeable with deuterium), 9.66 (m, 1H, exchangeable withdeuterium); MS (ion spray) 662 (M+1); Anal. Calc'd for C₃₆H₄₈N₆O₆: C,65.43; H, 7.32; N, 12.72. Found: C, 65.14; H, 7.09; N, 12.91.

Trifluoroacetic acid (7 mL) was added to a solution of the product ofPreparation 363 (4.05 g, 6.13 mmol) in 18 mL of dichloromethane and theresulting clear brown solution was stirred at ambient temperature for 4h. The mixture was poured into 300 mL of saturated sodium bicarbonateand extracted with ethyl acetate (1×150 mL). The yellow brown colororganic layer was separated and the aqueous layer was saturated withsodium chloride and extracted with fresh ethyl acetate. The aqueouslayer was discarded. The organic extracts were combined, washed withbrine, dried over anhydrous sodium sulfate, filtered, and concentratedto give 3.48 g (99%) of diastereomeric mixture of the desired product(free base form) as a white foam: ¹H-NMR (δ, DMSO) 1.15-1.25 (m, 6H),1.45-1.95 (m, 8H), 2.45-2.60 (m, 2H), 2.97-3.07 (m, 1H), 3.25-3.45 (m,2H), 3.47-3.60 (m, 1H), 3.77 (s, 3H), 4.27-4.37 (m, 1H), 6.36 (s, 1H),6.98 (d, J=8.7 Hz, 2H), 7.10-7.18 (m, 3H), 7.20-7.30 (m, 2H), 7.35 (d,J=8.7 Hz, 2H), 7.42 (s, 1H), 7.65 (s, 1H), 8.10 (br s, 1H, exchangeablewith deuterium), 10.10 (s, 1H, exchangeable with deutrium); MS (ionspray) 562 (M+1); Anal. Calc'd for C₃₁H₄₀N₆O₄ 0.5 H₂O: C, 65.35; H,7.25; N, 14.75. Found: C, 65.39; H, 7.27; N, 14.12.

Example 206

82 mg (0.146 mmol) of the product of Example 205 was dissolved in 2 mLof 1N HCl and diluted with 2 mL of deionized water and the resultingslightly turbid solution was freeze-dried to give 89.5 mg (97%) of thedesired product as a off-white crystalline solid: ¹H-NMR (δ, DMSO)consistent with the structure; MS (ion spray) 562 (Free base) (M+1);Anal. Calc'd for C₃₁H₄₀N₆O₄ H₂O: C, 57.14; H, 6.50; N, 12.90. Found: C,57.35; H, 6.77; N, 12.89.

To a solution of phthalide (6.0 g, 44.8 mmol) in ethanol (150 mL) wasadded pyrrolidine (15.0 mL, 180 mmol) and the mixture stirred for 48 hat ambient temperature. The mixture was then concentrated and theresidue purified by flash chromatography (silica gel, ethyl acetate) toyield 8.50 g (92 %) of the desired product as an oil. ESMS: (M+1)⁺206.2.¹H NMR (DMSO-d₆) δ7.53-7.45 (m, 1H), 7.42-7.33 (m, 1H), 7.31-7.25 (m,1H), 7.23-7.17 (m, 1H), 5.11 (t, J=5.65 Hz, 1H), 4.44 (d, J=5.65 Hz,2H), 3.45 (t, J=6.78 Hz, 2H), 3.09 (t,J=6.78 Hz, 2H), 1.92 (m, 4H).Anal. Calcd. for C₁₂H₁₅NO₂.0.1EtOAc: C, 69.57; H, 7.44; N, 6.54. Found:C, 69.67; H, 7.41; N, 6.54.

The compound from Preparation 363 (2.05 g, 10.0 mmol) was combined with4-nitroimidazole (1.13 g, 10.0 mmol) and triphenylphosphine (2.62 g,10.0 mmol) in tetrahydrofuran (75 mL) and the mixture cooled in an icebath. Diethyl-azodicarboxylate (2.00 mL, 13.0 mmol) was then added viasyringe and the mixture stirred overnight while warming to ambienttemperature. The mixture was concentrated and the residue purified byflash chromatography (silica gel, ethyl acetate) to provide 1.16 g ofthe desired product as a yellow solid: ESMS: (M+1)⁺301.2; ¹H NMR wasconsistent with product.

The product of Preparation 364 (0.50 g, 1.7 mmol) was added to a mixtureof 10% palladium/carbon (0.20 g) and palladium/black (0.05 g) intetrahydrofuran (30 mL) and the mixture shaken under hydrogen (40 psi)in a Parr apparatus. After the reduction was complete, the reactionmixture was filtered through celite and the filtrate immediatelycombined with 1,3-dicyclohexylcarbodiimide (0.344 g, 1.7 mmol),1-hydroxybenzotriazole mono-hydrate (0.225 g, 1.7 mmol), and the productof Preparation 1d, (0.633 g, 1.7 mmol). After stirring overnight atambient temperature, the mixture was concentrated and the resultingresidue slurried in ethyl acetate and filtered. The filtrate wasconcentrated and the residue purified by flash chromatography (silicagel, chloroform/methanol) which provided 0.68 g (64 %) of product as awhite solid.

ESMS: (M+1)³⁰ 633.2, 634.2.¹H NMR was consistent with product. Anal.Calcd. for C₃₄H₄₄N₆O₆: C, 64.54; H, 7.01; N, 13.28. Found: C, 64.78; H,7.21; N, 13.31.

Example 207

To a solution of the compound from Preparation 365 (0.58 g, 0.92 mmol)stirring in dichloromethane (20 mL) at room temperature was addedtrifluoroacetic acid (5 mL). After stirring for 1.5 h, the reactionmixture was concentrated and the residue treated with excess aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate andchloroform. The extracts were concentrated and the residue purified byflash chromatography (silica gel, chloroform/methanol) to give 0.40 g ofthe product. ESMS: (M+1)⁺ 533.3, 534.0. ¹H NMR was consistent withproduct.

Anal. Calcd. for C₂₉H₃₆N₆O₄. 0.23CHCl₃: C, 62.68; H, 6.52; N, 15.00.Found: C, 62.84; H, 6.56; N, 14.62.

To a solution of phthalide (2.10 g, 15.7 mmol) in ethanol (50 mL) wasadded dimethyl amine (40 % aqueous, 5.0 mL, 40 mmol) and the mixturestirred for 72 hours at ambient temperature. The mixture was thenconcentrated and the residue purified by flash chromatography (silicagel, ethyl acetate) to yield 1.46 g (52%) of the desired product as anoil. ESMS: (M+1)⁺ 180.1. ¹H NMR was consistent with product.

To the compound from Preparation 366 (1.40 g, 9.0 mmol) was dissolved indichloromethane (25 mL) followed by the addition of triethylamine (1.25mL, 9.0 mmol). Then methane sulfonylchloride (0.70 mL, 9.0 mmol) wasadded dropwise via syringe and the resulting mixture stirred for 0.5 hat ambient temperature. The mixture was then concentrated and theresidue combined with potassium carbonate (1.24 g, 18.0 mmol) and4-nitroimidazole (1.02 g, 9.0 mmol) in dimethylformamide (25 mL) andthis mixture stirred overnight at ambient temperature. The mixture wasconcentrated and combined with water followed by extraction with ethylacetate. Concentration of the combined extracts left crude product whichwas purified by flash chromatography (silica gel, chloroform/methanol)to give 0.40 g (15%) of the desired product: ESMS: (M+1)⁺ 275.3. ¹H NMR(300 MHz, DMSO-d₆) δ8.33 (d, J=1.51 Hz, 1H), 7.85(d, J=1.51 Hz, 1H),7.50-7.37 (m, 3H), 7.35-7.28 (m, 1H), 5.24 (s, 2H), 2.97 (s, 3H), 2.65(s, 3H).

Anal. Calcd. for C₁₃H₁₄N₄O₃: C, 56.92; H, 5.14; N, 20.43. Found: C,57.17; H, 5.16; N, 20.40.

The product of Preparation 367 (1.70 g, 6.2 mmol) was added to a mixtureof 10% palladium/carbon (1.2 g) and palladium/black (0.5 g) intetrahydrofuran (100 mL) and the mixture shaken under hydrogen (38 psi)in a Parr apparatus. After the reduction was complete, the reactionmixture was filtered through celite and the filtrate immediatelycombined with 1,3-dicyclohexylcarbodiimide (1.28 g, 6.2 mmol),1-hydroxybenzotriazole mono-hydrate (0.840 g, 6.2 mmol), and the productof Preparation 1j, (2.35 g, 6.2 mmol). After stirring overnight atambient temperature, the mixture was concentrated and the resultingresidue slurried in ethyl acetate and filtered. The filtrate wasconcentrated and the residue purified by flash chromatography (silicagel, chloroform/methanol) which provided 3.35 g (88%) of product as awhite foam. ESMS: (M+1)⁺605.4, 606.5. ¹H NMR was consistent withproduct.

Example 208

To a solution of the compound from Preparation 368 (3.30 g, 5.5 mmol)stirring in dichloromethane (40 mL) at room temperature was addedtrifluoroacetic acid (10 mL). After stirring for 2.5 h, the reactionmixture was concentrated and the residue treated with excess aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate and thecombined extracts were dried over sodium sulfate and concentrated. Theresidue was purified by flash chromatography (silica gel,chloroform/methanol) to give 1.10 g of the product as an off whitesolid: ESMS: (M+1)⁺505.2, 506.4. ¹H NMR was consistent with product.

Anal. Calcd. for C₂₈H36N₆O₃.0.1CHCl₃: C, 65.34;H, 7.04; N, 16.27. Found:C, 65.67; H, 7.08; N, 15.94.

Methyl-3-bromomethyl benzoate (6.08 g, 26.5 mmol) was combined with4-nitroimidazole (3.00 g, 26.5 mmol) and potassium carbonate (9.04 g,26.5 mmol) in dimethylformamide (75 mL) and the mixture stirredovernight at ambient temperature. The mixture was then concentrated andthe residue taken up in water and extracted with chloroform.

The combined extracts were dried over sodium sulfate and concentratedleaving a residue which was purified by flash chromatography (silicagel, chloroform/methanol) to give 5.77 g (83%) of product as an offwhite solid. ESMS: (M+1)⁺ 262.2; ¹H NMR (300 MHz, DMSO-d₆) δ8.54 (s,1H), 8.05 (s, 1H), 8.02 (d, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.69 (d, J=7.7Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 5.41 (s, 2H) 3.87 (s, 3H). Anal. Calcd.for: C₁₂H₁₁N₃O₄.0.15CHCl₃: C, 65.54; H, 7.33; N, 13.90. Found: C, 65.41;H, 7.37; N, 13.48.

To a solution of Preparation 369 (4.00 g, 15.3 mmol) in ethanol (5 mL)and tetrahydrofuran (10 mL) was added sodium hydroxide (50 mL of 2 Naqueous solution) and the mixture stirred at ambient temperature untilhydrolysis was complete. The aqueous mixture was acidified to pH 2.0with aqueous hydrochloric acid and the organics extracted with ethylacetate. Concentration left the crude acid which was combined with1,3-dicyclohexylcarbodiimide (3.15 g, 15.3 mmol), 1-hydroxybenzotriazolemono-hydrate (2.06 g, 15.3 mmol), and dimethylamine (40% aqueous, 1.75mL, 14.0 mmol) in tetrahydrofuran (75 mL) and the mixture stirredovernight at ambient temperature. The mixture was concentrated and theresulting residue slurried in ethyl acetate and filtered. The filtratewas concentrated and the residue purified by flash chromatography(silica gel, chloroform/methanol) which provided 2.50 g (60%) of thedesired product as a tan solid. ESMS: (M+1)⁺ 275.3; ¹H NMR (300 MHz,DMSO-d₆) δ8.54 (d, J=1.25 Hz, 1H), 8.3 (d, J=1.25 Hz, 1H), 7.50-7.32 (m,4H), 5.34 (s, 2H), 2.97 (s, 3H), 2.87 (s, 3H). Anal. Calcd. for:C₁₂H₁₁N₃O₄: C, 56.93; H, 5.14; N, 20.43. Found: C, 57.21; H, 5.34; N,20.36.

The product of Preparation 370 (1.0 g, 4.0 mmol) was added to a mixtureof 10% palladium/carbon (0.80 g) and palladium/black (0.30 g) intetrahydrofuran (100 mL) and the mixture shaken under hydrogen (39 psi)in a Parr apparatus.

After the reduction was complete, the reaction mixture was filteredthrough celite and the filtrate immediately combined with1,3-dicyclohexylcarbodiimide (0.824 g, 4.0 mmol), 1-hydroxybenzotriazolemono-hydrate (0.540 g, 4.0 mmol), and the product of Preparation 1j,(1.51 g, 4.0 mmol). After stirring overnight at ambient temperature, themixture was concentrated and the resulting residue slurried in ethylacetate and filtered. The filtrate was concentrated and the residuepurified by flash chromatography (silica gel, chloroform/methanol) whichprovided 2.05 g (84%) of the desired product as a white solid. ESMS:(M+1)⁺ 605.4, 606.5. ¹H NMR was consistent with product. Anal. Calcd.for C₃₃H₄₄N₆O₅: C, 65.54; H, 7.33; N, 13.90. Found: C, 65.41; H, 7.37;N, 12.73.

Example 209

To a solution of the compound from Preparation 371 (2.00 g, 3.3 mmol)stirring in dichloromethane (30 mL) at room temperature was addedtrifluoroacetic acid (10 mL). After stirring for 2 h, the reactionmixture was concentrated and the residue treated with excess aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate and thecombined extracts were dried over sodium sulfate and concentrated. Theresidue was purified by flash chromatography (silica gel,chloroform/methanol) to give pure free base. This material was dissolvedin minimal ethyl acetate/methanol and treated with diethyl ethersaturated with hydrochloric acid. Concentration left a semi-solid whichwas taken up in chloroform, concentrated, and dried to give 0.765 g of alight yellow solid. ESMS: (M+1)⁺ 505.2, 506.4. ¹H NMR was consistentwith product.

Anal. Calcd. for: C₂₈H₄₁N₆O₃.1CHCl₃: C, 49.98; H, 5.64; N, 12.06. Found:C, 49.51; H, 6.14; N, 11.67.

Triethylphosphonoacetate (13.44 g, 60 mmol) was dissolved intetrahydrofuran (100 mL) and the mixture cooled, under a nitrogenatmosphere, to −50° C. in a dry ice/acetone bath.

Then n-butyllithium (37.5 mL, 1.6 M in hexanes, 60 mmol) was added viasyringe and the mixture stirred at −40 to −50° C. for 20 min. before theaddition of o-tolualdehyde (6.0 g, 50 mmol). After stirring for 3 h andwarming to 10° C., the mixture was quenched with water and the productextracted with ethyl acetate. The combined extracts were dried oversodium sulfate and concentrated yielding an oil which was purified byflash chromatography (silica gel, ethyl acetate) to net 9.25 g (97%) ofthe desired product. FDMS: (M+) 190.1. ¹H NMR (DMSO-d₆) δ7.88 (d,J=15.83 Hz, 1H), 7.71 (d, J=7.91 Hz, 1H), 7.35-7.15 (m, 3H), 6.50 (d,J=15.83 Hz, 1H), 4.19 (q, J=7.16 Hz, 2H), 2.39 (s, 3H), 1.26 (t, J=7.16Hz, 3H).

Anal. Calcd. for C₁₂H₁₄O₂.0.1EtOAc: C, 74.82; H, 7.49. Found: C, 74.65;H, 7.75.

The product from Preparation 372 (3.00 g, 15.8 mmol) was dissolved incarbontetrachloride (50 mL) and N-bromosuccinimide (2.82 g, 15.8 mmol)and 2,2′-azobisisobutyronitrile (cat. 50 mg) were added. This mixturewas heated at reflux for 7 h after which the mixture was cooled andfiltered. The filtrate was concentrated and added together withpotassium carbonate(4.40 g, 31.9 mmol) and 4-nitroimidazole (1.78 g,15.8 mmol)in dimethylformamide (75 mL). After stirring for 72 h, themixture was concentrated, water added, and extracted with ethyl acetate.The combined extracts were concentrated and the resulting residuepurified by flash chromatography(chloroform/methanol) to give 2.60 g(55%) of the product as an oil. ESMS: (M+1)⁺ 302.3.

¹H NMR (300 MHz, DMSO-d₆) δ8.32 (d, J=1.5 Hz, 1H), 7.95 (d, J=15.6 Hz,1H), 7.86 (d, J=1.5 Hz, 1H), 7.84-7.70 (m, 1H), 7.50-7.38 (m, 2H),7.19-7.12 (m, 1H), 6.54 (d, J=15.6 Hz, 1H), 5.59 (s, 2H), 4.20 (q, J=7.0Hz, 2H), 1.27 (t, J=7.0 Hz,3H). Anal. Calcd. for C₁₅H₁₅N₃O₄: C, 55.31;H, 4.64; N, 12.69. Found: C, 55.37; H, 4.75; N, 12.80.

To a solution of Preparation 373 (2.50 g, 8.3 mmol) in ethanol (5 mL)and tetrahydrofuran (10 mL) was added sodium hydroxide (30 mL of 2 Naqueous solution) and the mixture stirred at ambient temperature untilhydrolysis was complete. The aqueous mixture was acidified to pH 1.8with aqueous hydrochloric acid and extracted with ethyl acetate.Concentration left the 2.20 g of the acid as a tan solid.ESMS: (M+1)⁺264.2. ¹H NMR(300 MHz, DMSO-d₆) δ12.58 (bs, 1H), 8.32 (s, 1H), 7.90 (d,J=15.6 Hz, 1H), 7.87 (s, 1H), 7.80-7.70 (m, 1H), 7.50-7.37 (m, 2H),7.17-7.10 (m, 1H), 6.44 (d, J=15.6 Hz, 1H), 5.58 (s, 2H).

The acid (2.00 g, 7.3 mmol) was combined with1,3-dicyclo-hexylcarbodiimide (1.51 g, 7.3 mmol), 1-hydroxybenzotriazolemono-hydrate (0.98 g, 7.3 mmol), and dimethylamine (40% aqueous, 1.00mL, 8.0 mmol) in tetrahydrofuran (100 mL) and the mixture stirredovernight at ambient temperature. The mixture was concentrated and theresulting residue purified by flash chromatography (silica gel,chloroform/methanol) which provided 1.78 g (81%) of the desired amide.

ESMS: (M+1)⁺301.2, 302.3. Anal. Calcd. for C₁₅H₁₆N₄O₃: C, 59.99; H,5.37; N, 18.66. Found: C, 59.79; H, 5.34; N, 18.51.

The product of Preparation 374 (1.20 g, 4.0 mmol) was added to a mixtureof 10% palladium/carbon (0.95 g) and palladium/black (0.25 g) intetrahydrofuran (100 mL) and the mixture shaken under hydrogen (38 psi)in a Parr apparatus.

After the reduction was complete, the reaction mixture was filteredthrough celite and the filtrate immediately combined with1,3-dicyclohexylcarbodiimide (0.824 g, 4.0 mmol), 1-hydroxybenzotriazolemono-hydrate (0.540 g, 4.0 mmol), and the product of Preparation 1j,(1.51 g, 4.0 mmol). After stirring overnight at ambient temperature, themixture was concentrated and the resulting residue slurried in ethylacetate and filtered. The filtrate was concentrated and the residuepurified by flash chromatography (silica gel, chloroform/methanol) whichprovided 1.75 g (69%) of product as a yellow solid. ESMS: (M+1)⁺ 633.5,634.5. ¹H NMR was consistent with product. Anal. Calcd. forC₃₅H₄₈N₆O₅.0.2CHCl₃: C, 64.38; H, 7.40; N, 12.80. Found: C, 64.41; H,7.63; N, 12.14.

Example 210

To a solution of the compound from Preparation 375 (1.6 g, 2.5 mmol)stirring in dichloromethane (20 mL) at room temperature was addedtrifluoroacetic acid (5 mL). After stirring for 1 h, the reactionmixture was concentrated and the residue treated with excess aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate and thecombined extracts were dried over sodium sulfate and concentrated. Theresidue was purified by flash chromatography (silica gel,dichloromethane/methanol) to give the free base. This compound wasdissolved in minimal ethyl acetate and excess ether saturated withhydrochloric acid was added. Concentration and drying netted 0.53 g ofthe hydrochloride salt as a white solid. ESMS: (M+1)⁺ 533.2, 534.3. ¹HNMR was consistent with product.

Anal. Calcd. for C₃₀H₃₉N₆O₃.3HCl: C, 59.99; H, 5.37; N, 18.66. Found: C,59.79; H, 5.34; N, 18.51.

To 3-aminobenzyl alcohol (3.00 g, 24.4 mmol) in dichloromethane(55 mL)was added triethylamine (17 mL, 122 mmol) and 4-dimethylaminopyridine(cat. 50 mg) and the mixture cooled to 0° C. under a nitrogenatmosphere. Then methanesulfonyl chloride (9.4 mL, 122 mmol) was addeddropwise via syringe and the resulting mixture stirred for 2 h whilewarming to ambient temperature. The mixture was concentrated in vacuoand the residue taken up in dimethylformamide (100 mL)and solidpotassium carbonate (20 g, 146 mmol) added along with 4-nitro-imidazole(2.75 g, 24.3 mmol). This mixture stirred at ambient temperature for 90h after which the mixture was concentrated and the residue taken up inwater and the product extracted with ethyl acetate. The combinedextracts were washed with water and dried over sodium sulfate.Concentration left a semi-solid which was tritruated in chloroform andfiltered to yield the desired bis-sulfonamide (3.5 g, 38%)as a whitesolid. ESMS: (M+1)⁺ 375.2. ¹H NMR (300 MHz, DMSO-d₆) δ8.51 (d, J=1.13Hz, 1H), 8.02 (d, J=1.13 Hz, 1H), 7.65-7.45 (m, 4H), 5.36 (s, 2H) 3.54(s, 6H).

To a solution of Preparation 376 (0.75 g, 2.0 mmol) in ethanol (3 mL)and tetrahydrofuran (3 mL) was added sodium hydroxide (10 mL of 2 Naqueous solution) and the mixture stirred at ambient temperature untilhydrolysis was complete. The aqueous mixture was acidified to pH 3.5with aqueous hydrochloric acid and the organics extracted with ethylacetate. Concentration left a residue which was purified by flashchromatography (silica gel, chloroform/methanol) which afforded 0.41 g(69%) of pure product as a yellow solid. ESMS: (M+1)⁺ 297.4; ¹H NMR (300MHz, DMSO-d₆) δ9.81 (s, 1H), 8.47 (d, J=1.51 Hz, 1H), 7.98 (d, J=1.51Hz, 1H), 7.40-7.30(m, 1H), 7.20-7.00 (m, 3H), 5.31 (s, 2H), 3.00 (s,3H). Anal. Calcd. for C₁₁H₁₂N₄O₄S: C, 44.59; H, 4.08; N, 18.91. Found:C, 44.12; H, 4.28; N, 18.90.

The product of Preparation 377 (0.55 g, 1.86 mmol) was added to amixture of 10% palladium/carbon (0.40 g) and palladium/black (0.15 g) intetrahydrofuran (50 mL) and the mixture shaken under hydrogen (40 psi)in a Parr apparatus. After the reduction was complete, the reactionmixture was filtered through celite and the filtrate immediatelycombined with 1,3-dicyclohexylcarbodiimide (0.384 g, 1.86 mmol),1-hydroxybenzotriazole mono-hydrate (0.251 g, 1.86 mmol), the product ofPreparation 1j, (0.70 g, 1.85 mmol), and additional tetrahydrofuran (30mL). After stirring overnight at ambient temperature, the mixture wasconcentrated and the resulting residue slurried in ethyl acetate andfiltered. The filtrate was concentrated and the residue purified byflash chromatography (silica gel, chloroform/methanol) which provided0.66 g (57%) of the desired product as a white solid. ESMS: (M+1)⁺627.4, 628.5. ¹H NMR was consistent with product.

Example 211

To a solution of the compound from Preparation 379 (0.60 g, 0.96 mmol)stirring in dichloromethane (25 mL) at room temperature was addedtrifluoroacetic acid (5 mL). After stirring for 2 h, the reactionmixture was concentrated and the residue treated with excess aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate and thecombined extracts were dried over sodium sulfate and concentrated. Theresidue was purified by flash chromatography (silica gel,chloroform/methanol) to give 0.25 g of the desired pure product as awhite solid.

ESMS: (M+1)⁺ 527.2, 528.3. ¹H NMR was consistent with product.

Anal. Calcd. for C₂₆H₃₄N₆O₄S: C, 59.30; H, 6.51; N, 15.96. Found: C,59.13; H, 6.65;.N, 15.66.

The product of Preparation 377 (0.60 g, 2.03 mmol) was added to amixture of 10% palladium/carbon (0.50 g) and palladium/black (0.10 g) intetrahydrofuran (40 mL) and the mixture shaken under hydrogen (39 psi)in a Parr apparatus. After the reduction was complete, the reactionmixture was filtered through celite and the filtrate immediatelycombined with 1,3-dicyclohexylcarbodiimide (0.418 g, 2.03 mmol),1-hydroxybenzotriazole mono-hydrate(0.274 g, 2.03 mmol), the product ofPreparation 1d, (0.77 g, 2.03 mmol), and additional tetrahydrofuran (40mL). After stirring overnight at ambient temperature, the mixture wasconcentrated and the resulting residue slurried in ethyl acetate andfiltered. The filtrate was concentrated and the residue purified byflash chromatography (silica gel, chloroform/methanol) which provided0.28 g (22%) of the desired product as a light tan solid. ¹H NMR wasconsistent with product.

Example 212

To a solution of the compound from Preparation 380 (0.28 g, 0.44 mmol)stirring in dichloromethane (10 mL) at room temperature was addedtrifluoroacetic acid (2.5 mL). After stirring for 2.5 h, the reactionmixture was concentrated and the residue treated with excess aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate and thecombined extracts were dried over sodium sulfate and concentrated. Theresidue was purified by flash chromatography (silica gel,chloroform/methanol) to give 45 mg of the desired product as an offwhite solid.

ESMS: (M+1)⁺ 529.2. ¹H NMR was consistent with product.

Anal. Calcd. for C₂₅H₃₂N₆O₅S.2H₂O: C, 53.18; H, 6.43; N, 14.88. Found:C, 53.40; H, 6.30; N. 13.53.

To a solution of 3-isochromanone (3.00 g, 20.0 mmol) in ethanol (40 mL)was added dimethyl amine (40% aqueous, 3.0 mL, 24 mmol) and the mixturestirred for 72 hours at ambient temperature. The mixture was thenconcentrated and the residue purified by flash chromatography (silicagel, chloroform/methanol) to yield 3.16 g (81%) of the desired productas an oil. ESMS: (M+1)⁺ 194.3. ¹H NMR (DMSO-d₆) δ7.40-7.34 (m, 1H),7.25-7.13 (m, 2H), 7.09-7.03 (m, 2H), 5.04 (t, J=5.3 Hz, 1H), 4.44 (d,J=5.3 Hz, 2H), 3.72 (s, 2H), 3.02 (s, 3H), 2.85 (s, 3H).

To the compound from Preparation 381 (2.00 g, 10.4 mmol) was dissolvedin dichloromethane (40 mL) followed by the addition of triethylamine(1.74 mL, 12.5 mmol). Then methane sulfonylchloride (0.96 mL, 12.5 mmol)was added dropwise via syringe and the resulting mixture stirred for 2.5h at ambient temperature. The mixture was then concentrated and theresidue combined with potassium carbonate (2.85 g, 20.6 mmol) and4-nitroimidazole (1.17 g, 10.4 mmol) in dimethylformamide (50 mL) andthis mixture stirred overnight at ambient temperature. The mixture wasconcentrated and combined with water followed by extraction with ethylacetate. Concentration of the combined extracts left crude product whichwas purified by flash chromatography (silica gel, chloroform/methanol)to give 0.88 g of the desired product as a light solid.

ESMS: (M+1)⁺ 289.1. ¹H NMR (300 MHz, DMSO-d₆) δ8.32 (s, 1H), 7.88 (s,1H), 7.30-7.05 (m, 4H), 5.27 (s, 2H), 3.85 (s, 2H), 3.06 (s, 3H), 2.82(s, 3H). Anal. Calcd. for C₁₄H₁₆N₄O₃.0.05CHCl₃: C, 57.35; H, 5.50; N,19.04. Found: C, 57.10; H, 5.53; N, 18.80.

The product of Preparation 382 (0.75 g, 2.6 mmol) was added to a mixtureof 10% palladium/carbon (0.60 g) and palladium/black (0.15 g) intetrahydrofuran (40 mL) and the mixture shaken under hydrogen (37 psi)in a Parr apparatus.

After the reduction was complete, the reaction mixture was filteredthrough celite and the filtrate immediately combined with1,3-dicyclohexylcarbodiimide (0.537 g, 2.6 mmol), 1-hydroxybenzotriazolemono-hydrate (0.351 g, 2.6 mmol), and the product of Preparation 1j,(0.983 g, 2.6 mmol). After stirring overnight at ambient temperature,the mixture was concentrated and the resulting residue slurried in ethylacetate and filtered. The filtrate was concentrated and the residuepurified by flash chromatography (silica gel, chloroform/methanol) whichprovided 0.87 g (84%) of product as a tan foam.

ESMS: (M+1)⁺ 619.7, 620.8. ¹H NMR was consistent with product.

Example 213

To a solution of the compound from Preparation 383 (0.80 g, 1.3 mmol)stirring in dichloromethane (15 mL) at room temperature was addedtrifluoroacetic acid (3 mL). After stirring for 1 h, the reactionmixture was concentrated and the residue treated with excess aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate and thecombined extracts were dried over sodium sulfate and concentrated. Theresidue was purified by flash chromatography (silica gel,dichloromethane/methanol) to give 0.14 g of the desired product as awhite solid.

ESMS: (M+1)⁺ 519.3, 520.4. ¹H NMR was consistent with product. Anal.Calcd. for C₂₉H₃₈N₆O₃.0.2CHCl₃: C, 65.48; H, 7.23; N, 15.69. Found: C,65.06; H, 7.29; N, 15.62.

To a solution of 5-flouro-2-methylbenzoic acid (9.00 g, 58.4 mmol) inmethanol (200 mL) was added tosic acid mono-hydrate (cat. 0.50 g) andthe mixture heated overnight at reflux. The mixture was thenconcentrated and the residue purified by flash chromatography (silicagel, chloroform/methanol) to yield 5.80 g of the desired ester as anoil.

ESMS: (M+1)⁺ 167.9; ¹H NMR (300 MHz, DMSO-d₆) δ7.56 (dd, J=9.4 and 2.6Hz, 1H), 7.40-7.33 (m, 2H), 3.83 (s, 3H), 2.48 (s, 3H).

The product from Preparation 384 (5.30 g, 31.5 mmol) was dissolved incarbontetrachloride (75 mL) and N-bromosuccin-imide (5.60 g, 31.5 mmol)and 2,2′-azabisisobuytronitrile (cat. 70 mg) were added. This mixturewas heated at reflux for 4 h after which the mixture was cooled andfiltered. The filtrate was concentrated and added together withpotassium carbonate (5.00 g, 36.2 mmol) and 4-nitroimidazole (3.56 g,31.5 mmol) in dimethylformamide (50 mL). After stirring for overnight atambient temperature, the mixture was concentrated, water added, andextracted with ethyl acetate. The combined extracts were concentratedand the resulting residue purified by flash chromatography(chloroform/methanol) to give 6.25 g of product as a white solid. ESMS:(M+1)⁺ 280.1. ¹H NMR (300 MHz, DMSO-d₆) δ8.36 (d, J=1.51 Hz, 1H), 7.90(d, J=1.51 Hz, 1H), 7.73 (dd, J=9.42 and 2.64 Hz, 1H), 7.57-7.45 (m,1H), 7.35-7.25 (m, 1H), 5.60 (s, 2H), 3.87 (s, 3H). Anal. Calcd. forC₁₂H₁₀N₃O₄F: C, 51.62; H, 3.61; N, 15.05. Found: C, 52.19; H, 3.75; N,14.87.

To a solution of Preparation 385 (3.25 g, 11.6 mmol) in ethanol (5 mL)and tetrahydrofuran (5 mL) was added sodium hydroxide (25 mL of 2 Naqueous solution) and the mixture stirred at ambient temperature untilhydrolysis was complete. The aqueous mixture was acidified to pH 2.5with aqueous hydrochloric acid and the organics extracted with ethylacetate. Concentration left the crude acid as a solid. The acid (2.30 g,8.7 mmol) was combined with 1,3-dicyclo-hexylcarbodiimide (1.79 g, 8.7mmol), 1-hydroxybenzotriazole mono-hydrate (1.17 g, 8.7 mmol), anddimethylamine (40% aqueous, 2.00 mL, 40.0 mmol) in tetrahydrofuran (60mL) and the mixture stirred overnight at ambient temperature. Themixture was concentrated and the resulting residue slurried in ethylacetate and filtered. The filtrate was concentrated and the residuepurified by flash chromatography (silica gel, chloroform/methanol) whichprovided for recovery of the desired amide, 1.85 g.

ESMS: (M+1)⁺ 293.1. ¹H NMR (300 MHz, DMSO-d₆) δ8.32 (d, J=1.51 Hz, 1H),7.84 (d, J=1.51 Hz, 1H), 7.55-7.45 (m, 1H), 7.35-7.20 (m, 2H), 5.21 (s,2H), 2.96 (s, 3H), 2.65 (s, 3H).

The product of Preparation 386 (0.60 g, 2.0 mmol) was added to a mixtureof 10% palladium/carbon (0.50 g) and palladium/black (0.10 g) intetrahydrofuran (100 mL) and the mixture shaken under hydrogen (38 psi)in a Parr apparatus. After the reduction was complete, the reactionmixture was filtered through celite and the filtrate immediatelycombined with 1,3-dicyclohexylcarbodiimide (0.422 g, 2.0 mmol),1-hydroxybenzotriazole mono-hydrate (0.277 g, 2.0 mmol), and the productof Preparation 1j, (0.775 g, 2.0 mmol). After stirring 72 h at ambienttemperature, the mixture was concentrated and the resulting residueslurried in ethyl acetate and filtered. The filtrate was concentratedand the residue purified by flash chromatography (silica gel,chloroform/methanol) which provided 0.78 g (62%) of product. ESMS:(M+1)⁺ 623.5. ¹H NMR was consistent with product.

Example 214

To a solution of the compound from Preparation 386A (0.65 g, 1.0 mmol)stirring in dichloromethane (20 mL) at room temperature was addedtrifluoroacetic acid (4 mL). After stirring for 2 h, the reactionmixture was concentrated and the residue treated with excess aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate and thecombined extracts were dried over sodium sulfate and concentrated. Theresidue was purified by flash chromatography (silica gel,dichloromethane/methanol) to give 0.05 g of the desired product. ESMS:(M+1)⁺ 523.4, 524.5. ¹H NMR was consistent with product. Anal. Calcd.for C₂₈H₃₅N₆O₃F.0.4CHCl₃: C, 63.86; H, 6.70; N, 15.93. Found: C, 64.28;H, 6.96; N, 15.54.

Potassium carbonate (6.90 g, 50 mmol) was combined with 4-nitroimidazole(5.65 g, 50 mmol) and 2-cyanobenzyl bromide (9.80 g, 50 mmol) indimethylformamide (100 mL) and the mixture stirred overnight at ambienttemperature.

The mixture was then concentrated and the residue taken up in water andextracted with ethyl acetate. The combined extracts were dried oversodium sulfate and concentrated leaving a tan solid which was purifiedby flash chromatography (silica gel, chloroform/methanol) to give 9.76 g(85%) of product. ESMS: (M+1)⁺ 229.3. ¹H NMR (300 MHz, DMSO-d₆) δ8.42(d, J=1.51 Hz, 1H), 7.95 (d, J=1.51 Hz, 1H), 7.92 (dd, J=7.91 Hz, 1.13Hz, 1H), 7.77-7.69 (m, 1H), 7.60-7.52 (m, 1H), 7.31 (d, J=7.91 Hz, 1H),5.57 (s, 2H). Anal. Calcd. for C₁₁H₉N₄O₂: C, 57.89; H, 3.53; N, 24.55.Found: C, 57.65; H, 3.53; N, 24.33.

The compound of Preparation 387 (2.50 g, 11 mmol) was dissolved intetrahydrofuran (40 mL) and borane added (1.0 M in tetrahydrofuran, 15mL, 15 mmol) and the mixture stirred overnight at ambient temperature.The reaction was then quenched by the slow addition of methanol. Afterhydrogen evolution had ceased, the mixture was concentrated and theresidue purified by flash chromatography (silica gel,chloroform/methanol). Recovered 0.61 g (17%) of the desired amine as alight oil.

ESMS: (M+1)⁺ 233.1. ¹H NMR (300 MHz, DMSO-d₆) δ8.42 (d, J=1.13 Hz, 1H),7.96 (d, J=1.13 Hz, 1H), 7.43 (d, J=7.16 Hz, 1H), 7.38-7.15 (m, 2H),7.09 (d, J=7.16 Hz, 1H), 5.42 (s, 2H), 3.81 (s,2H), 3.30 (bs, 2H).

The amine from Preparation 388 (0.90 g, 3.88 mmol) was dissolved intetrahydrofuran (40 mL) and methyl isocyanate (0.50 mL, 8.5 mmol) wasadded dropwise via syringe and the mixture stirred overnight at ambienttemperature. The resulting precipitate was filtered and dried whichnetted 0.89 g, (79%) of the desired urea.ESMS: (M+1)⁺ 290.2. ¹H NMR (300MHz, DMSO-d₆) δ8.35 (d, J=1.51 Hz, 1H), 7.92 (d, J=1.51 Hz, 1H),7.37-7.20 (m, 3H), 7.12 (d, J=7.54 Hz, 1H), 6.45-6.35 (m, 1H), 5.90-5.78(m, 1H), 5.39 (s, 2H), 4.28 (d, J=6.03 Hz, 2H), 2.56 (d, J=4.90 Hz, 3H).Anal. Calcd. for C₁₃H₁₅N₅O₃: C, 53.97; H, 5.23; N, 24.21. Found: C,53.71; H, 5.14; N, 24.10.

The product of Preparation 389 (0.50 g, 1.73 mmol) was added to amixture of 10% palladium/carbon (0.40 g) and palladium/black (0.10 g) intetrahydrofuran (80 mL) and the mixture shaken under hydrogen (39 psi)in a Parr apparatus.

After 6 h, the reaction mixture was filtered through celite to removecatalyst and undissolved starting material (0.15 g, poor solubility).The filtrate was immediately combined with 1,3-dicyclohexylcarbodiimide(0.356 g, 1.73 mmol), 1-hydroxybenzotriazole mono-hydrate (0.233 g, 1.73mmol), and the product of Preparation 1d, (0.657 g, 1.73 mmol). Afterstirring for 72 h at ambient temperature, the mixture was concentratedand the resulting residue slurried in ethyl acetate and filtered. Thefiltrate was concentrated and the residue purified by flashchromatography (silica gel, chloroform/methanol) which provided 0.25 gof product.

ESMS: (M+1)⁺ 622.5. ¹H NMR was consistent with product.

Example 215

To a solution of the compound from Preparation 390 (0.24 g, 0.34 mmol)stirring in dichloromethane (10 mL) at room temperature was addedtrifluoroacetic acid (1.5 mL). After stirring for 2 h, the reactionmixture was concentrated and the residue treated with excess aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate. Theextracts were concentrated and the residue purified by flashchromatography (silica gel, chloroform/methanol) to give 0.065 g ofproduct as a white solid. ESMS: (M+1)⁺ 522.3, 523.5. ¹H NMR wasconsistent with product.

To a solution of 2-aminobenzylamine, 3.0 g (24.6 mmol) in 50 mL ofmethanol and 15 mL of water at 0° C. was added 2.1 g of sodiumbicarbonate. The resulting slurry was stirred for 10 min. then 3.9 g ofthe product of Preparation 306 was added. The reaction mixture wasstirred overnight while slowly warming to ambient temperature and wasthen concentrated to dryness. The resulting residue was absorbed onto asilica pad and was chromatographed using 80% ethyl acetate/hexanes aseluant to yield 2.66 g (50%) of the desired product as an orange solid.¹H-NMR is consistent with structure; MS (ion spray) 219.2 (M+1); Anal.Calc'd for C₁₀H₁₀N₄O₂: C, 55.04; H, 4.62; N, 25.67. Found: C, 55.31; H,4.72; N, 25.76.

To a solution of the product of Preparation 391, 2.5 g (11.5 mmol) andtriethylamine, 4 mL (28.8 mmol) in 200 mL of dichloromethane at 0° C.was added 2.25 mL (28.8 mmol) of methanesulfonyl chloride. The resultingslurry was stirred overnight, slowly warming to ambient temperature andwas then concentrated to dryness. The residue was slurried in water andfiltered, then slurried in chloroform, filtered and dried under vacuumto yield 3.1 g (72%) of the desired product as a white solid. ¹H-NMR isconsistent with structure; MS (ion spray) 375.2 (M+1); Anal. Calc'd forC₁₂H₁₄N₄O₆S₂: C, 38.50; H, 3.77; N, 14.96. Found: C, 38.45; H, 3.66; N.14.74.

To a slurry of the prodcut of Preparation 392, 1.7 g (4.6 mmol) in 60 mLof absolute ethanol and 60 mL of tetrahydrofuran was added 23 mL (23mmol) of 1N sodium hydroxide. The resulting solution was stirred 90 minthen was concentrated to dryness. The residue was partitioned betweenethyl acetate and water and acidified to pH=3 with 1N HCl. The mixturewas extracted with ethyl acetate. The combined organics were washed withbrine, dried over sodium sulfate, filtered and concentrated to dryness.The residue was chromatographed on silica gel using a gradient of 3-10%methanol/chloroform as eluant to yield 0.7 g (51%) of the desiredproduct as a yellow solid. ¹H-NMR is consistent with structure; MS (ionspray) 297.4 (M+1); Anal. Calc'd for C₁₁H₁₂N₄O₄S: C, 44.59; H, 4.08; N,18.91. Found: C, 44.38; H, 4.23; N, 18.65.

A solution of the product of Preparation 393, 0.59 g (2.0 mmol) in 40 mLof tetrahydrofuran was added to a slurry of 10% palladium on carbon (1.0g) in 40 mL of tetrahydrofuran. The mixture was hydrogenated at 40 psifor 40 min, then filtered through celite. To this solution was added0.76 g (2.0 mmol) of the product of Preparation 1d, 0.3 g (2.2 mmol) of1-hydroxybenzotriazole and 0.46 g (2.2 mmol) of dicylohexylcarbodiimide.The reaction mixture was stirred overnight at ambient temperature andwas then concentrated to dryness. The residue was partitioned betweenethyl acetate and water and was then extracted with ethyl acetate. Thecombined organics were washed with brine, dried over sodium sulfate,filtered and concentrated to dryness. The residue was chromatographed onsilica gel using a gradient of 3-10% methanol/chloroform to yield 0.45 g(36%) of the desired product as a tan foam. ¹H-NMR is consistent withstructure; MS (ion spray) 629.3 (M+1).

Example 216

To a solution of the product of Preparation 394, 0.35 g (0.56 mmol) in12 mL of dichloromethane was added 4 mL of trifluoroacetic acid. Theresulting mixture was stirred for 1 h, then was concentrated to dryness.The residue was partitioned between ethyl acetate and saturated sodiumbicarbonate and was then extracted with ethyl acetate. The combinedorganics were washed with brine, dried over sodium sulfate, filtered andconcentrated to dryness. To a solution of the residue in chloroform wasadded HCl-saturated ether. The slurry was concentrated to dryness toyield 0.34 g (100%) of the desired product as a tan solid. ¹H-NMR isconsistent with structure; MS (ion spray) 529.2 (M+1); Anal. Calc'd forC₂₅H₃₂N₆O₅S.2.3HCl: C, 49.03; H, 5.64; N, 13.72. Found: C, 48.94; H,5.62; N, 13.39.

To a solution of 4-nitroimidazole (12.76 g, 112.8 mmol) in anhydrousdimethylformamide (350 mL) was added sodium hydride (4.96 g, 124.1 mmol,60% in mineral oil), followed by ethyl bromoacetate dropwise over aperiod of five minutes, and the reaction was stirred at room temperatureovernight. The solution was concentrated and the residue was dissolvedin a solution of 20% isopropanol in chloroform, washed with 1N HCl,dried over magnesium sulfate, and concentrated to give 35.0 g crudeproduct as an orange solid. These solids were treated with anhydrousdiethyl ether (100 mL), sonicated, heated on a steam bath, and cooled ina 0° C. refrigerator overnight. The mixture was filtered and the solidswashed with ice cold diethyl ether, then dried to give 16.56 g of thetitle compound as a white solid, 74% yield: ¹H NMR (d⁶-DMSO, δ): 1.19(t, J=6.1 Hz, 3H), 4.15 (q, J=6.1 Hz, 2H), 5.02 (s, 2H), 7.80 (s, 1H),8.32 (s, 1H); MS (ion spray) 200 (M⁺+1).

To a mixture of 4.0 g 10% palladium on carbon in 100 mL tetrahydrofuranwas added the product of Preparation 395 (9.96 g, 50.0 mmol). Themixture was subjected to 60 psi hydrogen on a Parr apparatus for 2 h,then filtered through celite to remove the catalyst. The filtrate wasconcentrated and the resulting oil was dissolved in anhydrousdimethylformamide (10 mL). This solution was added to a solution of theproduct of Preparation 1d from Examples Part 2A (20.92 g, 55.0 mmol) and1-hydroxybenzotriazole (8.42, 55.0 mmol) in anhydrous dimethylformamide(150 mL) which had been cooled to −13° C. in an ice/acetone bath.Dicyclohexyl carbodiimide (11.35 g, 55.0 mmol) was then added, and thestirred solution was allowed to warm to room temperature overnight. Thesolvent was removed, ethyl acetate was added, and the insolubledicyclohexyl urea was removed by filtration. The filtrate was washedwith 1N HCl, saturated aqueous sodium bicarbonate solution, brine, driedover magnesium sulfate, and concentrated. Purification by flashchromatography on silica gel (eluting with 5% methanol/dichloromethane)gave 5.39 g of the title compound as a tan solid, 31% yield: ¹H NMR(d⁶-DMSO, δ): 1.17 (t, J=6.1 Hz, 3H), 1.25 (m, 15H), 3.55 (q, J=3.7 Hz,1H), 3.65 (m, 1H), 4.08 (q, J=3.7 Hz, 2H), 4.40 (s, 2H), 4.56 (brs, 1H),4.84 (s, 2H), 7.15 (s, 1H), 7.22 (m, 6H), 7.38 (s, 1H), 7.42 (m, 1H),10.10 (brs, 1H): MS (ion spray) 532 (M⁺+1).

To a solution of the product of Preparation 396 (7.17 g, 13.49 mmol) indioxane (100 mL) was added a solution of lithium hydroxide (623 mg,14.84 mmol) in water (50 mL). After 1 h, more lithium hydroxide (60 mg,1.42 mmol) was added. After 30 min, the reaction was quenched with 1NHCl and concentrated. The resulting oil was dissolved in a 20%isopropanol/chloroform solution, washed with 1N HCl, water, dried overmagnesium sulfate, and concentrated to give 6.12 g of the title compoundas a golden yellow solid, 90% yield: ¹H NMR (d⁶-DMSO, δ): 1.32 (m, 15H),3.62 (m, 1H), 3.73 (m, 1H), 4.48 (s, 2H), 4.62 (brs, 1H), 4.85 (s, 2H),7.19 (s, 1H), 7.30 (m, 6H), 7.51 (m, 1H), 7.59 (s, 1H), 10.24 (brs, 1H):MS (ion spray) 504 (M⁺+1).

To a solution of L-proline (5.38 g, 25.0 mmol) in anhydroustetrahydrofuran (75 mL) was added carbonyl diimidazole (4.05 g 25.0mmol), and the solution stirred at room temperature. After 30 minutes,benzylamine (2.73 mL, 25.0 mmol) was added dropwise, and the reactionstirred at room temperature overnight. The solvent was removed and theresidue dissolved dichloromethane, washed with 1N HCl, saturated aqueoussodium bicarbonate solution, brine, dried over magnesium sulfate, andconcentrated to give 6.29 g of a white solid. This solid dissolved indiethyl ether saturated with dry HCl_((g)) (35 mL, ˜3N in HCl) andstirred vigorously at room temperature for 2 h. The volatiles wereremoved and the residue dissolved in 20% isopropanol/chloroform, washedwith saturated aqueous sodium bicarbonate solution, dried over magnesiumsulfate, and concentrated to give 2.7 g of the title compound as ayellow oil, 64% yield: ¹H NMR (d⁶-DMSO, δ): 1.55 (m, 1H), 1.62 (m, 1H),1.90 (m, 1H), 2.75 (m, 2H), 3.00 (brs, 1H), 3.23 (brs, 1H), 3.48 (m,1H), 4.20 (d, J=5.4 Hz, 2H), 7.17 (m, 3H), 7.22 (t, J=5.0 Hz, 2H), 8.34(s, 1H); MS(ion spray) 205 (M⁺+1).

To a 0° C. solution of the product of Preparation 396A (1.01 g, 2.0mmol) in anhydrous tetrahydrofuran (10 mL) was added the product ofPreparation 397 (409 mg, 2.0 mmol), 1-hydroxybenzotriazole (322 mg, 2.1mmol), and dicyclohexyl carbodiimide (433 mg, 2.1 mmol). The stirredreaction was allowed to warm to room temperature overnight. Theinsoluble dicyclohexyl urea was removed by filtration, and the filtratewas concentrated. The resulting foam was dissolved in ethyl acetate,washed with 1N HCl, saturated aqueous sodium bicarbonate solution,brine, dried over magnesium sulfate, and concentrated. Purification byflash chromatography on silica gel (eluting with 4-7%methanol/dichloromethane) gave 636 mg of the title compound as a faintlyyellow solid, 46% yield: ¹H NMR (d⁶-DMSO, δ): 1.32 (m, 15H), 1.93 (m,4H), 2.07 (m, 1H), 3.50 (m, 1H), 3.64 (m, 1H), 3.72 (m, 1H), 4.28 (d,J=6.3 Hz, 2H), 4.34 (m, 2H), 4.47 (s, 2H), 4.63 (brs, 1H), 4.93 (s, 2H),7.21 (d, J=12.5 Hz, 2H), 7.30 (m, 10H), 7.45 (s, 1H), 8.38 (m, 1H),10.16 (brs, 1H): MS (ion spray) 690 (M⁺+1). Anal. (C₃₆H₄₇N₇O₇): H,N;C:calcd 62.68, found 62.13.

Example 217

To a solution of the product of Preparation 398 (627 mg, 0.91 mmol) wasadded acetic acid saturated with HCl_((g)) (20 mL, ˜3N in HCl) and thesolution stirred vigorously at room temperature for 2 h. The solutionwas concentrated toluene was added and the mixture concentrated toassist in removal of acetic acid. The resulting white solid was treatedwith diethyl ether, sonicated, and 700 mg yellow solid was isolated byfiltration. The solid was dried overnight to give 626 mg of the titlecompound as a yellow powder, 100% yield: ¹H NMR (d⁶-DMSO, δ): consistentwith structure; MS (ion spray) 590 (M⁺+1 of free base); Anal.(C₃₁H₄₄N₇O₇Cl): C,H; N: calcd. 14.81, found 13.83.

To a solution of L-proline (5.38 g, 25.0 mmol) in anhydroustetrahydrofuran (75 mL) was added carbonyl diimidazole (4.05 g 25.0mmol), and the solution stirred at room temperature. After 30 min,aniline (2.28 mL, 25.0 mmol) was added dropwise, and the reactionstirred at room temperature overnight. The solvent was removed and theresidue dissolved in dichloromethane, washed with 1N HCl , saturatedaqueous sodium bicarbonate solution, brine, dried over magnesiumsulfate, and concentrated to give 6.30 g of a white solid. The solid wasdissolved in dichloromethane (50 mL) and treated with trifluoroaceticacid (15 mL). The solution was stirred vigorously at room temperaturefor lh. The volatiles were removed and the residue dissolved indichloromethane, washed with saturated aqueous sodium bicarbonatesolution, dried over magnesium sulfate, and concentrated to give 1.62 gof the title compound as a white solid, 39% yield: ¹H NMR (d⁶-DMSO, δ):consistent with structure; MS(ion spray) 191 (M⁺+1)

To a solution of the product of Preparation 396A (504 mg, 1.00 mmol) inanhydrous tetrahydrofuran (20 mL) was added the product of Preparation399 (173 mg, 0.91 mmol), PyBOP® (473 mg, 0.91 mmol), anddiisopropylethyl amine (0.48 mL, 2.73 mmol). The reaction was stirred atroom temperature overnight. The solution was concentrated and theresulting residue was dissolved in ethyl acetate, washed with 1N HCl,saturated aqueous sodium bicarbonate solution, brine, dried overmagnesium sulfate, and reconcentrated. Purification by flashchromatography on silica gel (eluting with 4-7%methanol/dichloromethane) gave 244 mg of the title compound as an orangesolid, 40% yield: 1H NMR (d⁶-DMSO, δ): consistent with structure; MS(ionspray) 676 (M⁺+1); Anal. (C₃₅H₄₅N₇O₇): C,H,N.

Example 218

To the product of Preparation 400 (234 mg, 0.35 mmol) was added aceticacid saturated with HCl_((g)) (10 mL, ˜3N in HCl) and the solutionstirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated to assistin removal of acetic acid. The residue was then treated with diethylether, sonicated, and 235 mg a light tan solid was isolated byfiltration. The solid was dried to give 230 mg of the title compound,100% yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure; MS(ionspray) 576 (M⁺+1 of free base); Anal. (C₃₀H₃₉N₇O₆Cl₂): C,H; N: theory14.71, found 14.13.

To a solution of L-proline (5.38 g, 25.0 mmol) in anhydroustetrahydrofuran (75 mL) was added carbonyl diimidazole (4.05 g 25.0mmol), and the solution stirred at room temperature. After 30 minutes,phenethylamine (3.14 mL, 25.0 mmol) was added dropwise, and the reactionstirred at room temperature overnight. The solvent was removed and theresidue dissolved in dichloromethane, washed with 1N HCl, saturatedaqueous sodium bicarbonate solution, brine, dried over magnesiumsulfate, and concentrated to give 6.77 g of a white solid. The solid wasdissolved in anhydrous dichloromethane (50 mL) and treated withtrifluoroacetic acid (15 mL). The solution was stirred vigorously atroom temperature for 1 h. The volatiles were removed and the residuedissolved in dichloromethane, washed with saturated aqueous sodiumbicarbonate solution , dried over magnesium sulfate, and concentrated togive 1.08 g of the title compound as a white solid, 23% yield: ¹H NMR(d⁶-DMSO, δ): consistent with structure; MS(ion spray) 219 (M⁺+1).

To a solution of the product of Preparation 396A (504 mg, 1.00 mmol) inanhydrous tetrahydrofuran (20 mL) was added the product of Preparation401 (198 mg, 0.91 mmol), PyBOP® (473 mg, 0.91 mmol), anddiisopropylethyl amine (0.48 mL, 2.73 mmol). The reaction was stirred atroom temperature overnight. The solution was concentrated and theresulting orange residue was dissolved in ethyl acetate, washed with 1NHCl, saturated aqueous sodium bicarbonate solution, brine, dried overmagnesium sulfate, and concentrated. Purification by flashchromatography on silica gel (eluting with 4-7%methanol/dichloromethane) gave 272 mg of the title compound as an lightorange solid, 42% yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure;MS(ion spray) 704 (M⁺+1); Anal. (C₃₇H₄₉N₇O₇): C,H,N.

Example 219

To the product of Preparation 402 (262 mg, 0.37 mmol) was added aceticacid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and the solutionstirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether to give 243 mg of thedesired compound, 94% yield: ¹H NMR (d⁶-DMSO, δ): consistent withstructure; MS(ion spray) 603 (M⁺+1 of free base); Anal. (C₃₂H₄₅N₇O₆Cl₂):C,H,N.

To a solution of the product of Preparation 396A (504 mg, 1.00 mmol) intetrahydrofuran (20 mL) was added S-alpha-methylbenzylamine (0.14 mL,0.91 mmol), PyBOP® (473 mg, 0.91 mmol), and diisopropylethyl amine (0.48mL, 2.73 mmol). The reaction was stirred at room temperature overnight.The solution was concentrated and the resulting orange residue wasdissolved in dichloromethane, washed with 1N HCl, saturated aqueoussodium bicarbonate solution, brine, dried over magnesium sulfate, andconcentrated. Purification by flash chromatography on silica gel(eluting with 5% methanol/dichloromethane) gave 232 mg of the titlecompound as a white solid, 42% yield: ¹H NMR (d⁶-DMSO, δ): consistentwith structure; MS(ion spray) 607 (M⁺+1); Anal. (C₃₂H₄₂₉N₆O₆): H,N; C:theory 63.35, found 62.64.

Example 220

To the product of Preparation 403 (222 mg, 0.37 mmol) was added aceticacid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and the solutionstirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether and sonicated to give 218 mgof the title compound as a tan solid, 100% yield: ¹H NMR (d⁶-DMSO, δ):consistent with structure; MS(ion spray) 607 (M⁺+1 of free base); Anal.(C₂₇H₃₆N₆O₄Cl₂): C,H,N.

To a solution of the product of Preparation 396A (504 mg, 1.00 mmol) intetrahydrofuran (20 mL) was added S-alpha-methylbenzylamine (0.14 mL,0.91 mmol), PyBOP® (benzotriazol-1-yl-oxytripyrrolidinephosphoniumhexafluorophosphate) (473 mg, 0.91 mmol), and diisopropylethyl amine(0.48 mL,2.73 mmol). The reaction was stirred at room temperatureovernight. The solution was concentrated and the resulting orangeresidue was dissolved in dichloromethane, washed with 1N HCl, saturatedaqueous sodium bicarbonate solution, brine, dried over magnesiumsulfate, and reconcentrated. Purification by flash chromatography onsilica gel (eluting with 15% methanol/1:1 diethyl ether:hexane) gave 168mg of the title compound as a white solid, 30% yield: ¹H NMR (d⁶-DMSO,δ): consistent with structure; MS(ion spray) 607 (M⁺+1).

Example 221

To the product of Preparation 404 (164 mg, 0.237 mmol) was added aceticacid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and the mixturestirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated to assistin removal of acetic acid. The residue was then treated with diethylether, sonicated, and 161 mg of the title compound was isolated byfiltration as a yellow solid, 100% yield: ¹H NMR (d6-DMSO, δ):consistent with structure; MS(ion spray) 507 (M⁺+1 of free base); Anal.(C₂₇H₃₆N₆O₄Cl₂): C,H; N: theory 14.06, found 13.15.

To a solution of the product of Preparation 396A (504 mg, 1.00 mmol) intetrahydrofuran (20 mL) was added 1,2,3,4-tetrahydroisoquinoline (0.13mL, 0.91 mmol), PyBOP® (473 mg, 0.91 mmol), and diisopropylethyl amine(0.48 mL, 2.73 mmol). The reaction was stirred at room temperatureovernight. The solution was concentrated and the resulting orangeresidue was dissolved in dichloromethane, washed with 1N HCl, saturatedaqueous sodium bicarbonate solution, brine, dried over magnesiumsulfate, and reconcentrated. Purification by flash chromatography onsilica gel (eluting with 5% methanol/dichloromethane) gave 560 mg of thetitle compound as a yellow solid, 99% yield: ¹H NMR (d⁶-DMSO, δ):consistent with structure; MS (ion spray) 619 (M⁺+1).

Example 222

To the product of Preparation 405 (583 mg, 0.94 mmol) was added aceticacid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and the mixturestirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated to assistin removal of acetic acid. The residue was then treated with diethylether, sonicated, and 573 mg of the title compound was isolated byfiltration as a yellow solid, 100% yield: ¹H NMR (d⁶-DMSO, δ):consistent with structure; Ion spray MS (M⁺+1 of free base): 519; Anal.(C₂₇H₃₇N₆O₄Cl₃): C,N; H: calcd 5.94, found 6.68.

To a solution of the product of Preparation 396A (504 mg, 1.00 mmol) inanhydrous tetrahydrofuran (20 mL) was added indoline (0.10 mL, 0.91mmol), PyBOP® (473 mg, 0.91 mmol), and diisopropylethyl amine (0.48 mL,2.73 mmol). The reaction was stirred at room temperature overnight. Thesolution was concentrated and the resulting orange residue was dissolvedin dichloromethane, washed with 1N HCl, saturated aqueous sodiumbicarbonate solution, brine, dried over magnesium sulfate, andreconcentrated. Purification by flash chromotography on silica gel(eluting with 4-7% methanol/dichloromethane) gave 543 mg of the titlecompound as a yellow solid, 99% yield: ¹H NMR (d⁶-DMSO, δ): consistentwith structure; MS(ion spray) 605 (M⁺+1).

Example 223

To the product of Preparation 406 (534 mg, 0.88 mmol) was added aceticacid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and the mixturestirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated to assistin removal of acetic acid. The residue was then treated with diethylether, sonicated, and 336 mg of the title compound was isolated byfiltration as a yellow solid, 62% yield: ¹H NMR (d⁶-DMSO, δ): consistentwith structure; MS(ion spray) 505 (M⁺+1 of free base); Anal.(C₂₇H₃₅N₆O₄Cl₃): C,H,N.

To a solution of D-proline (1.08 g, 5.0 mmol) in anhydroustetrahydrofuran (20 mL) was added carbonyl diimidazole (0.81 g, 5.0mmol), and the solution stirred at room temperature. After 30 min,benzylamine (0.55 mL, 5.0 mmol) was added dropwise, and the reactionstirred at room temperature overnight. The solvent was removed and theresidue dissolved in dichloromethane, washed with 1N HCl, saturatedaqueous sodium bicarbonate solution, brine, dried over magnesiumsulfate, and concentrated to give 1.31 g of a white solid. This solidwas dissolved in dichloromethane (20 mL) and treated withtrifluoroacetic acid (5 mL). The reaction was stirred vigorously at roomtemperature for 1 h. The mixture was concentrated and the residuedissolved in 20% isopropanol/chloroform, washed with saturated aqueoussodium bicarbonate solution, dried over magnesium sulfate, andconcentrated to give 600 mg of the title compound as a yellow oil, 59%yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure; MS(ion spray) 205(M⁺+1).

To a solution of the product of Preparation 396A (504 mg, 1.00 mmol) intetrahydrofuran (20 mL) was added the product of Preparation 407 (186mg, 0.91 mmol), PyBOP® (473 mg, 0.91 mmol), and diisopropylethyl amine(0.48 mL, 2.73 mmol). The reaction was stirred at room temperatureovernight. The solution was concentrated and the resulting orangeresidue was dissolved in 20% isopropanol/chloroform, washed with 1N HCl,saturated aqueous sodium bicarbonate solution, brine, dried overmagnesium sulfate, and reconcentrated. Purification by flashchromatography on silica gel (eluting with 5-10%methanol/dichloromethane) gave 454 mg of the title compound as a whitesolid, 72% yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure; MS(ionspray) 690 (M⁺+1); Anal. (C₃₆H₄₇N₇O₇): H,N;C: calcd 62.68, found 61.72.

Example 224

To the product of Preparation 408 (441 mg, 0.64 mmol) was added aceticacid saturated with HCl_((g)) (20 mL, ˜3N in HCl) and the solutionstirred vigorously at room temperature for 2h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether, sonicated, and 459 mg ofwhite solid was isolated by filtration. The solid was dried to give 431mg of the title compound as a white powder, 96% yield: ¹H NMR (d⁶-DMSO,δ): consistent with structure; MS(ion spray) 590 (M⁺+1); Anal.(C₃₁H₄₂N₇O₅Cl3): C,H,N.

To a solution of D-proline (1.08 g, 5.0 mmol) in anhydroustetrahydrofuran (20 mL) was added carbonyl diimidazole (0.81 g, 5.0mmol), and the solution stirred at room temperature. After 30 minutes,aniline (0.46 mL, 5.0 mmol) was added dropwise, and the reaction stirredat room temperature overnight. The solvent was removed and the residuedissolved in dichloromethane, washed with 1N HCl, saturated aqueoussodium bicarbonate solution, brine, dried over magnesium sulfate, andconcentrated to give 1.20 g of a white solid. This solid was dissolvedin anhydrous dichloromethane (10 mL) and treated with trifluoroaceticacid (10 mL). The reaction was stirred vigorously at room temperaturefor 1 h. The volatiles were removed and the residue dissolved in 20%isopropanol/chloroform, washed with saturated aqueous sodium bicarbonatesolution, dried over magnesium sulfate, and concentrated to give 281 mgof the title compound as a white solid, 46% yield: ¹H NMR (d⁶-DMSO, δ):1.60 (p, J=8.6 Hz, 2H), 1.73 (m, 1H), 1.98 (m, 1H), 2.82 (t, J=7.6 Hz,2H), 3.30 (brs, 1H), 3.63 (dd, J=7.6, 4.3 Hz, 1H), 6.99 (t, J=8.2 Hz,1H), 7.22 (t, J=8.2 Hz, 2H), 7.59 (d, J=8.2 Hz, 1H); MS(ion spray) 191(M⁺+1).

To a solution of the product of Preparation 396A (619 mg, 1.23 mmol) indimethylformamide (25 mL) was added the product of Preparation 409 (281mg, 1.48 mmol), PyBOP® (640 mg, 1.23 mmol), and diisopropylethyl amine(0.44 mL, 2.50 mmol). The reaction was stirred at room temperatureovernight. The solution was concentrated and the resulting residue wasdissolved in dichloromethane, washed with 0.1N HCl, saturated aqueoussodium bicarbonate solution, brine, dried over magnesium sulfate, andreconcentrated. Purification by flash chromatography on silica gel(eluting with 3-6% methanol/dichloromethane) gave 265 mg of the titlecompound as a yellow solid, 32% yield: ¹H NMR (d⁶-DMSO, δ): consistentwith structure. MS(ion spray) 676 (M⁺+1).

Example 225

To the product of Preparation 410 (262 mg, 0.39 mmol) was added aceticacid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and the mixturestirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture. The residue was thentreated with diethyl ether, sonicated, to provide 267 mg of the desiredproduct by a tan solid which was dried to give 225 mg of the titlecompound, 87% yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure;MS(ion spray) 576 (M⁺+1 of free base); Anal. (C₃₀H₄₁N₇O₆Cl₂): C,H,N.

To a solution of L-proline (1.08 g, 5.0 mmol) in anhydroustetrahydrofuran (20 mL) was added carbonyl diimidazole (0.81 g, 5.0mmol), and the solution stirred at room temperature. After 30 minutes,phenethylamine (0.63 mL, 5.0 mmol) was added dropwise, and the reactionstirred at room temperature overnight. The solvent was removed and theresidue dissolved in dichloromethane, washed with 1N HCl, saturatedaqueous sodium bicarbonate solution, brine, dried over magnesiumsulfate, and concentrated to give 1.39 g of a white solid. This solidwas dissolved in anhydrous dichloromethane (10 mL) and treated withtrifluoroacetic acid (10 mL). The reaction was stirred vigorously atroom temperature for 1 h. The volatiles were removed and the residuedissolved in 20% isopropanol/chloroform, washed with saturated aqueoussodium bicarbonate solution, dried over magnesium sulfate, andconcentrated to give 386 mg of the title compound as a yellow oil, 35%yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure; MS(ion spray) 219(M⁺+1).

To a solution of the product of Preparation 396A (360 mg, 0.71 mmol) indimethylformamide (25 mL) was added the product of Preparation 411 (156mg, 0.71 mmol), PyBOP® (372 mg, 0.71 mmol), and diisopropylethyl amine(0.25 mL, 1.42 mmol). The reaction was stirred at room temperatureovernight. The solution was concentrated and the resulting orangeresidue was dissolved in dichloromethane, washed with 0.1N HCl,saturated aqueous sodium bicarbonate solution, brine, dried overmagnesium sulfate, and reconcentrated. Purification by flashchromatography on silica gel (eluting with 4-8%methanol/dichloromethane) gave 304 mg of the title compound as a lighttan solid, 60% yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure;MS(ion spray) 704 (M⁺+1).

Example 226

To the product of Preparation 412 (262 mg, 0.37 mmol) was added aceticacid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and the mixturestirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether, sonicated, and 281 mg ofthe title compound was isolated by filtration as a yellow solid, 92%yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure; MS(ion spray) 604(M⁺+1 of free base); Anal. (C₃₂H₄₄N₇O₅Cl₃): C,H; N: calcd 13.75, found12.96.

To a solution of L-proline (5.38 g, 25.0 mmol) in anhydroustetrahydrofuran (75 mL) was added carbonyl diimidazole (4.05 g, 25.0mmol), and the solution stirred at room temperature. After 30 min,p-methoxybenzylamine (3.26 ml, 25.0 mmol) was added dropwise, and thereaction stirred at room temperature overnight. The solvent was removedand the residue dissolved in dichloromethane, washed with 1N HCl,saturated sodium bicarbonate solution, dried over magnesium sulfate, andconcentrated. The resulting solids were dissolved in anhydrousdichloromethane (50 mL) and treated with trifluoroacetic acid (20 mL).The reaction was stirred vigorously at room temperature for 1 h. Thevolatiles were removed and the residue dissolved in dichloromethane,washed with saturated aqueous sodium bicarbonate solution, dried overmagnesium sulfate, and concentrated to give 0.95 g of the title compoundas a yellow oil, 16% yield: ¹H NMR (d⁶-DMSO, δ): consistent withstructure; MS(ion spray) 235 (M⁺+1).

To a solution of the product of Preparation 396A (1.01 g, 2.0 mmol) inanhydrous tetrahydrofuran (10 mL) was added the product of Preparation413 (469 mg, 2.0 mmol), 1-hydroxybenzotriazole (322 mg, 2.1 mmol), anddicyclohexyl carbodiimide (433 mg, 2.1 mmol). The reaction was stirredat room temperature overnight then filtered and concentrated. Theresulting orange residue was dissolved in dichloromethane, washed with1N HCl, saturated aqueous sodium bicarbonate solution, brine, dried overmagnesium sulfate, and reconcentrated. Purification by flashchromatography on silica gel (eluting with 10% methanol/dichloromethane)gave 370 mg of the title compound as a light yellow foam, 26% yield: ¹HNMR (d⁶-DMSO, δ): consistent with structure; MS(ion spray) 720 (M⁺+1).;Anal. (C₃₇H₄₉N₇O₈): H,N; C: calcd 61.74, found 60.96.

Example 227

To the product of Preparation 414 (360 mg, 0.50 mmol) was added aceticacid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and the solutionstirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether and sonicated to give 349 mgof the title as a yellow solid, 99% yield: ¹H NMR (d⁶-DMSO, δ):consistent with structure; MS(ion spray) 620 (M⁺+1 of free base); Anal.(C₃₂H₄₆N₇O₇Cl): C,H; N: calcd 14.16, found 13.26.

To a solution of 5-amino-2-napthol (7.96 g, 50.0 mmol) in anhydroustetrahydrofuran (200 mL) was added benzyl chloroformate (7.14 mL, 50.0mL) and diisopropylethylamine (9.6 mL, 55.0 mmol). The reaction wasstirred at room temperature overnight. The reaction was quenched with0.1N HCl, concentrated, treated with anhydrous diethyl ether (150 mL),and 11.49 g of gray solid was isolated by filtration. This material wasdissolved in anhydrous tetrahydrofuran (120 mL), cooled to −13° C. in anice/acetone bath, treated with sodium hydride (60% dispersion in mineraloil, 1.88 g, 47.0 mmol), and stirred for 30 min. To this solution wasadded a solution of methyl iodide (2.6 mL, 41.0 mmol) in tetrahydrofuran(30 mL) and the reaction was allowed to warm to room temperatureovernight. The reaction was quenched with 0.1N HCl and concentrated. Theresulting residue was dissolved in dichloromethane, washed with 1N HCl,saturated aqueous sodium bicarbonate solution, dried over magnesiumsulfate, and reconcentrated. Purification by flash chromatography onsilica gel (eluting with 20% ethyl acetate/hexane) followed bysonication in diethyl ether gave 2.66 g of the title compound as a whitesolid, 17% yield: ¹H NMR (d⁶-DMSO, d): consistent with structure; MS(ionspray) 308 (M⁺+1).

To a solution of 5% palladium on carbon (1.00 g) in anhydroustetrahydrofuran (45 mL) and acetic acid (45 mL) was added the product ofPreparation 415 (2.66 g, 8.65 mmol). The mixture was subjected to 60 psihydrogen on a Parr apparatus for 2 h, then filtered through celite toremove the catalyst. The solvent was removed and the resulting black oilwas dissolved in dichloromethane, washed with saturated aqueous sodiumbicarbonate solution, dried over magnesium sulfate, and concentrated.Purification by flash chromatography on silica gel (eluting with 20%ethyl acetate/hexanes) gave 537 mg of the title compound as a purplesolid, 36% yield: ¹H NMR (d⁶-DMSO, d): consistent with structure; MS(ionspray) 619 (M⁺+1).

To a solution of the product of Preparation 396A (1.01 g, 2.0 mmol) intetrahydrofuran (20 mL) was added the product of Preparation 416 (346mg, 2.0 mmol), 1-hydroxybenzotriazole (322 mg, 2.1 mmol), anddicyclohexyl carbodiimide (433 mg, 2.1 mmol). The reaction was stirredat room temperature overnight. The insoluble dicyclohexyl urea wasremoved by filtration, and the filtrate concentrated. The resultingresidue was dissolved in ethyl acetate, washed with 1N HCl, saturatedaqueous sodium bicarbonate solution, brine, dried over magnesiumsulfate, and reconcentrated. Purification by flash chromatography onsilica gel (eluting with 5% methanol/dichloromethane) gave 372 mg of thetitle compound as a foam, 28% yield: ¹H NMR (d⁶-DMSO, d): consistentwith structure; MS(ion spray) 659 (M⁺+1); Anal. (C₃₅H₄₂N₆O₇): C,H,N.

Example 228

To a solution of the product of Preparation 417 (362 mg, 0.55 mmol) wasadded acetic acid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and themixture stirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether and sonicated to give 351 mgof the title compound as a lavender solid, 100% yield: ¹H NMR (d⁶-DMSO,d): consistent with structure; MS(ion spray) 559 (M⁺+1 of free base);Anal. (C₃₀H₃₉N₆O₇Cl): C,H,; N: calcd 13.32, found 11.61.

To a mixture of 1.0 g 10% palladium on carbon in 100 mL tetrahydrofuranwas added the product of Preparation 395 (1.78 g, 8.94 mmol). Themixture was subjected to 60 psi hydrogen on a Parr apparatus for 2 h,then filtered through celite to remove the catalyst. The majority ofsolvent was removed (50 mL of tetrahydrofuran remained) and to theresulting solution was added the product of Preparation from ExamplesPart 2A (3.78 g, 10.0 mmol), 1-hydroxybenzotriazole(1.53 g, 10.0 mmol),and dicyclohexyl carbodiimide (2.06 g, 10.0 mmol). The solution wasstirred at room temperature overnight. The insoluble dicyclohexyl ureawas removed by filtration and the solvent was removed. The resulting oilwas dissolved in ethyl acetate, washed with 1N HCl, saturated aqueoussodium bicarbonate solution, brine, dried over magnesium sulfate, andconcentrated. Purification by flash chromatography on silica gel(eluting with 6% methanol/dichloromethane) gave 3.17 g of the titlecompound as a yellow solid, 67% yield: ¹H NMR (d⁶-DMSO, d): consistentwith structure; MS(ion spray) 530 (M⁺+1); Anal. (C₂₇H₃₉N₅O₆): C,H; N:calcd 13.22, found 12.69.

A solution of the product of Preparation 418 (3.17 g, 5.99 mmol) indioxane (50 mL) was treated with a solution of lithium hydroxide (301mg, 7.18 mmol) in water (20 mL) and stirred vigorously. After 1 h, thereaction was quenched with 1N HCl, and concentrated. The resulting oilwas dissolved in ethyl acetate, washed with 1N HCl, water, brine, driedover magnesium sulfate, and concentrated to give 2.88 g of the titlecompound as a white foam, 96% yield: ¹H NMR (d⁶-DMSO, δ): consistentwith structure; MS(ion spray) 502 (M⁺+1).

To a solution of the product of Preparation 419 (1.0 g, 2.0 mmol)stirring in tetrahydrofuran (15 mL) was added the product of Preparation397 (409 mg, 2.0 mmol), 1-hydroxybenzotriazole (337 mg, 2.2 mmol), anddicyclohexyl carbodiimide (454 mg, 2.2 mmol). The reaction was allowedto warm to room temperature overnight. The insoluble dicyclohexyl ureawas removed by filtration, and the filtrate was concentrated. Theresulting foam was dissolved in ethyl acetate, washed with 1N HCl,saturated aqueous sodium bicarbonate solution, brine, dried overmagnesium sulfate, and concentrated. Purification by flashchromatography on silica gel (eluting with 4-7%methanol/dichloromethane) gave 794 mg of the title compound as a whitesolid, 58% yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure; MS(ionspray) 688 (M⁺+1).

Example 229

To the product of Preparation 420 (785 mg, 1.14 mmol) was added aceticacid saturated with HCl_((g)) (20 mL, ˜3N in HCl) and the mixturestirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether and sonicated to precipitategive 695 mg of the title compound as a light pink powder after drying,90% yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure; MS(ion spray)588 (M⁺+1 of free base); Anal. (C₃₂H₄₅N₇O₅Cl₂): H,N; C: calcd 56.63,found 57.53.

Example 230

To a solution of the product of Preparation 396A (504 mg, 1.0 mmol) inanhydrous acetonitrile (20 mL) was added benzylamine (0.11 mL, 1.0mmol), 1-hydroxy-7-azabenzo-triazole (150 mg, 1.1 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (211 mg, 1.1mmol). The reaction was stirred at room temperature overnight. Thesolution was concentrated and the resulting residue was dissolved indichloromethane, washed with 1N HCl, saturated aqueous sodiumbicarbonate solution, brine, dried over magnesium sulfate, andreconcentrated. Purification by flash chromatography on silica gel(eluting with 7% methanol/dichloromethane) gave 356 mg of a white solid.The solids were dissolved in acetic acid saturated with HCl_((g)) (20mL, ˜3N in HCl) and the mixture stirred vigorously at room temperaturefor 1 h. The solution was concentrated, toluene was added and themixture concentrated. The residue was then treated with diethyl etherand sonicated to precipitate 302 mg of the title compound as a light tansolid, 53% yield: ¹H NMR (d⁶-DMSO, δ): consistent with structure; MS(ionspray) 493 (M⁺+1 of free base); Anal. (C₂₆H₃₄N₆O₄Cl₂): C,H; N: calcd14.86, found 14.21.

To a solution of the product of Preparation 396A (504 mg, 1.0 mmol) inanhydrous acetonitrile (20 mL) was added(S)-(−)-N,alpha-dimethylbenzylamine (0.15 mL, 1.0 mmol),1-hydroxy-7-azabenzo-triazole (150 mg, 1.1 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (211 mg, 1.1mmol). The reaction was stirred at room temperature overnight. Thesolution was concentrated and the resulting residue was dissolved inethyl acetate, washed with 1N HCl, saturated aqueous sodium bicarbonatesolution, brine, dried over magnesium sulfate, and concentrated.Purification by flash chromatography on silica gel (eluting with 5%methanol/1:1 diethyl ether:hexane) gave 289 mg of the title compound asa white solid, 47% yield: ¹H NMR (d⁶-DMSO, δ): consistent withstructure; MS(ion spray) 621 (M⁺+1); Anal. (C₃₃H₄₄N6₇O₆) C,H,N.

Example 231

To a solution of the product of Preparation 421 (279 mg, 0.237 mmol) wasadded acetic acid saturated with HCl_((g)) (20 mL, ˜3N in HCl) and themixture stirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether and sonicated to precipitate235 mg of the title compound as a light red solid, 88% yield: ¹H NMR(d⁶-DMSO, δ): consistent with structure; MS(ion spray) 521 (M⁺+1 of freebase); Anal. (C₂₈H₃₈N₆O₄Cl₂): C,H; N: calcd 14.16, found 13.24.

To a solution of the product of Preparation 396A (400 mg, 0.79 mmol) inanhydrous acetnitrile (20 mL) was added N-benzylmethylamine (0.11 mL,0.87 mmol), 1-hydroxy-7-azabenzo-triazole (119 mg, 0.87 mmol), and1-ethyl-3-3-dimethylaminopropyl) carbodiimide hydrochloride (168 mg,0.87 mmol). The reaction was stirred at room temperature overnight. Thesolution was concentrated and the resulting residue was dissolved indichloromethane, washed with 1N HCl, saturated aqueous sodiumbicarbonate solution, brine, dried over magnesium sulfate, andreconcentrated. Purification by flash chromotography on silica gel(eluting with 2-7.5% methanol/dichloromethane) gave 122 mg of a whitesolid: ¹H NMR (d⁶-DMSO, δ): consistent with structure; MS(ion spray) 607(M⁺+1); Anal. (C₃₂H₄₂N₆O₆): H,N; C: calcd 63.35, found 62.77.

Example 232

To a solution of the product of Preparation 422 (110 mg, 0.18 mmol) wasadded acetic acid saturated with HCl_((g)) (20 mL, ˜3N in HCl) and themixture stirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether and sonicated to precipiate95 mg of the title compound as a white solid, 90% yield: ¹H NMR(d⁶-DMSO, δ): consistent with structure; MS(ion spray) 507 (M⁺+1 of freebase); Anal. (C₂₇H₃₆N₆O₄Cl₂): C,H; N: calcd 14.50, found 13.24.

To a solution of the product of Preparation 396A (504 mg, 1.0 mmol) inanhydrous tetrahydrofuran (20 mL) was added p-methoxybenzylamine (0.13mL, 1.0 mmol), 1-hydroxybenzotriazole (184 mg, 1.2 mmol), anddicyclohexyl carbodiimide (248 mg, 1.2 mmol). The reaction was stirredat room temperature overnight. Dicyclohexyl urea was removed byfiltration and the filtrate was concentrated. The resulting residue wasdissolved in dichloromethane, washed with 1N HCl, saturated aqueoussodium bicarbonate solution, brine, dried over magnesium sulfate, andreconcentrated. Purification by flash chromotography on silica gel(eluting with 2-7% methanol/dichloromethane) gave 236 mg of the titlecompound as a white solid, 38% yield: ¹H NMR (d⁶-DMSO, δ): consistentwith structure; MS(ion spray) 623 (M⁺+1); Anal. (C₃₂H₄₂N₆O₇): C,H,N.

Example 233

To the product of Preparation 423 (226 mg, 0.36 mmol) was added aceticacid saturated with HCl_((g)) (20 mL, ˜3N in HCl) and the mixturestirred vigorously at room temperature for 1 h. The solution wasconcentrated, toluene was added and the mixture concentrated. Theresidue was then treated with diethyl ether and sonicated to precipitate139 mg of the title compound as a white solid, 65% yield: ¹H NMR(d⁶-DMSO, δ): consistent with structure; MS(ion spray) 523 (M⁺+1 of freebase).

EXAMPLES PART 2C

To a stirring slurry of sodium hydride (0.66 g of a 60% dispersion inmineral oil, 16.5 mmol) in N,N-dimethylformamide (30 mL) at 0° C., wasadded a solution of 2-methyl-5-nitroimidazole (2.0 g, 15.7 mmol) inN,N-dimethylformamide (10 mL). This solution stirred at 0° C. for 10 minthen a solution of the product of Preparation 5 from Examples Part 1(4.21 g, 17.3 mmol) in N,N-dimethylformamide (10 mL) was added. Thereaction stirred for 3 h at room temperature, at which time it wasquenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate) and evaporatedin vacuo to provide a yellow oil. Flash chromatography (silica gel,10%-50% ethyl acetate/hexanes) yielded the desired product as alight-yellow solid (2.53 g, 60%): ¹H NMR consistent with structure; MS(IS) m/e 288 (M−1); Anal. Calc'd for C₁₄H₁₅N₃O₄: C, 58.13; H, 5.23; N,14.53. Found: C, 58.18; H, 5.26; N, 14.56.

To a suspension of 5% palladium on carbon (1.50 g) and dioxane (120 mL),in a Parr reaction bottle, was added the product of Preparation 424(2.70 g, 9.33 mmol) as a solid. The reaction bottle was placed on a Parrshaker, and shaken at room temperature for 2 h under a hydrogenatmosphere (35 psi). The reaction was filtered through a pad of Celite521 and the filtrate was then added to a previously prepared mixture ofthe product of Preparation 1d from Examples Part 1 (2.79 g, 7.34 mmol)and 1-hydroxybenzotriazole hydrate (1.10 g, 8.10 mmol) in 50 mL dioxaneat room temperature. This solution stirred for 15 min at which time1,3-dicyclohexylcarbodiimide (1.66 g, 8.10 mmol) was added. The reactionwas stirred for 16 h at room temperature, then the solvent wasevaporated under reduced pressure. The residue was dissolved in ethylacetate and filtered to remove the 1,3-dicyclohexylurea. The filtratewas purified by flash chromatography (silica gel, 50% ethylacetate/hexanes—ethyl acetate) to give the desired product as a tansolid foam (3.10 g, 68%): ¹H NMR consistent with structure; MS (IS) m/e622 (M+1); Anal. Calc'd for C₃₃H₄₃N₅O₇: C, 63.75; H, 6.97; N, 11.26.Found: C, 63.46; H, 6.92; N, 11.54.

To a solution of the product of Preparation 425 (2.85 g, 4.59 mmol) indioxane (100 mL) and water (50 mL) at room temperature was added lithiumhydroxide (0.55 g, 13.0 mmol). The reaction stirred 30 min at roomtemperature, at which time the dioxane was evaporated under reducedpressure. The residue was diluted with water and extracted with diethylether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light tan solid foam which was used without furtherpurification (2.64 g, 97%): ¹H NMR consistent with structure; MS (IS)m/e 594 (M+1); Anal. Calc'd for C₃₁H₃₉N₅O₇: C, 62.72; H, 6.62; N, 11.80.Found: C, 60.94; H, 6.40; N, 11.50.

To a solution of the product of Preparation 426 (0.70 g, 1.18 mmol) inanhydrous N,N-dimethylformamide (20 mL) at room temperature was added1-hydroxybenzotriazole hydrate (0.17 g, 1.22 mmol) and4-methylpiperidine (0.13 mL, 1.11 mmol). This mixture stirred for 15 minat room temperature, at which time 1,3-dicyclohexylcarbodiimide (0.25 g,1.22 mmol) was added. The reaction was stirred at room temperature for15 h, at which time it was quenched with brine and extracted with ethylacetate. The combined extracts were washed with brine, dried (sodiumsulfate) and evaporated to provide a light-brown solid foam. The foamwas dissolved in ethyl acetate, the 1,3-dicyclohexylurea was filteredaway and the filtrate was purified by flash chromatography (silica gel,75% ethyl acetate/hexanes—10% methanol/ethyl acetate) to give thedesired product as a light tan solid foam (0.475 g, 60%): ¹H NMRconsistent with structure; MS (IS) m/e 673 (M−1); Anal. Calc'd forC₃₇H₅₀N₆O₆: C, 65.85; H, 7.47; N, 12.45. Found: C, 65.20; H, 7.26; N,12.67.

Example 234

To a stirring solution of the product of Preparation 427 (0.41 g, 0.61mmol) and anisole (0.05 mL, 0.47 mmol) in anhydrous dichloromethane (25mL) at 0° C. was added trifluoroacetic acid (3 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled, saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—5%methanol/ethyl acetate—5% triethylamine/10% methanol/85% ethyl acetate)to provide the desired product as a white solid foam (0.26 g, 75%): ¹HNMR consistent with structure; MS (IS) m/e 574 (M+1); Anal. Calc'd forC₃₂H₄₂N₆O₄: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.64; H, 7.38; N,14.34.

To a solution of the product of Preparation 427 (0.70 g, 1.18 mmol) inanhydrous N,N-dimethylformamide (25 mL) at room temperature was added1-hydroxybenzotriazole hydrate (0.17 g, 1.22 mmol) and pyrrolidine (0.09mL, 1.11 mmol). This mixture stirred for 15 min at room temperature, atwhich time 1,3-dicyclohexylcarbodiimide (0.25 g, 1.22 mmol) was added.The reaction was stirred at room temperature for 15 h, at which time itwas quenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate) and evaporatedto provide a light-brown solid foam. The foam was dissolved in ethylacetate, the 1,3-dicyclohexylurea was filtered away and the filtrate waspurified by flash chromatography (silica gel, 75% ethylacetate/hexanes—10% methanol/ethyl acetate) to give the desired productas a light tan solid foam (0.58 g, 76%): ¹H NMR consistent withstructure; MS (IS) m/e 647 (M+1); Anal. Calc'd for C₃₅H₄₆N₆O₆: C, 65.00;H, 7.17; N, 12.99. Found: C, 63.16; H, 6.81; N, 12.91.

Example 235

To a stirring solution of the product of Preparation 428 (0.49 g, 0.76mmol) and anisole (0.05 mL, 0.47 mmol) in anhydrous dichloromethane (25mL) at 0° C. was added trifluoroacetic acid (3 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled, saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—5%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide the desired product as a white solid foam (0.27 g, 65%): ¹H NMRconsistent with structure; MS (IS) m/e 547 (M+1); Anal. Calc'd forC₃₀H₃₈N₆O₄: C, 65.91; H, 7.01; N, 15.37. Found: C, 65.37; H, 6.81; N,14.83.

To a 0° C. solution of 4-methylimidazole (5.00 g, 61 mmol) andconcentrated nitric acid (8.22 ml, 183 mmol) was added concentratedsulfuric acid (8.28 ml, 155 mmol), with stirring. After addition wascomplete, the ice bath was removed and the reaction was heated to agentle reflux for 2 h. The reaction was allowed to cool and then pouredinto ice water. The bright yellow precipitate was collected by vacuumfiltration and washed thoroughly with water to provide the desiredproduct as a pale yellow solid (5.28 g, 68%): ¹H NMR consistent withstructure; MS (FD) m/e 127 (M+); Anal. Calc'd for C₄H₅N₃O₂: C, 37.80; H,3.96; N, 33.06. Found: C, 37.73; H, 3.79; N, 33.32.

To a stirring slurry of sodium hydride (1.70 g of a 60% dispersion inmineral oil, 43 mmol) in N,N-dimethylformamide (50 mL) at 0° C., wasadded a solution of the product of Preparation 429 (5.15 g, 41 mmol) inN,N-dimethylformamide (50 mL). This solution stirred at 0° C. for 10 minthen a solution of the product of Preparation 5 from Examples Part 1(10.84 g, 45 mmol) in N,N-dimethylformamide (40 mL) was added. Thereaction stirred for 1.5 h at room temperature, at which time it wasquenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate)and evaporated toprovide a yellow oil, which contained a 9:1 mixture of the desiredregioisomer and the undesired 5-nitro-4-methyl regioisomer. Flashchromatography (silica gel, 25%-50% ethyl acetate/hexanes) yielded thedesired product as a light-yellow solid (7.14 g, 60%): ¹H NMR consistentwith structure; MS (IS) m/e 290 (M+1); Anal. Calc'd for C₁₄H₁₅N₃O₄: C,58.13; H, 5.23; N, 14.53. Found: C, 58.38; H, 5.33; N, 14.48.

To a suspension of 5% palladium on carbon (1.10 g) and dioxane (55 mL),in a Parr reaction bottle, was added the product of Preparation 430(1.55 g, 5.35 mmol) as a solid. The reaction bottle was placed on a Parrshaker, and shaken at room temperature for 3 h under a hydrogenatmosphere (40 psi). The reaction was filtered through a pad of Celite521 and the filtrate was then added to a previously prepared mixture ofthe product of Preparation 1d from Examples Part 2A(2.03 g, 5.35 mmol)and 1-hydroxybenzotriazole hydrate (0.80 g, 5.88 mmol) in 25 mL dioxaneat room temperature. This solution stirred for 15 min at which time1,3-dicyclohexylcarbodiimide (1.21 g, 5.88 mmol) was added. The reactionwas stirred at room temperature for 15 h, then the solvent wasevaporated under reduced pressure. The residue was dissolved in ethylacetate and the 1,3-dicyclohexylurea was filtered away. The filtrate waspurified by flash chromatography (silica gel, 50% ethylacetate/hexanes—ethyl acetate) to give the desired product as a lighttan solid foam (1.91 g, 57%): ¹H NMR consistent with structure; MS (IS)m/e 622 (M+1); Anal. Calc'd for C₃₃H₄₃N₅O₇: C, 63.75; H, 6.97; N, 11.26.Found: C, 62.75; H, 6.89; N, 11.76.

To a solution of the product of Preparation 431 (1.51 g, 2.41 mmol) indioxane (75 mL) and water (35 mL) at room temperature was added lithiumhydroxide (0.31 g, 7.24 mmol). The reaction stirred 25 min at roomtemperature, at which time the dioxane was evaporated under reducedpressure. The residue was diluted with water and extracted with diethylether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light tan solid foam that was used without furtherpurification (1.18 g, 83%): ¹H NMR consistent with structure; MS (IS)m/e 594 (M+1).

To a solution of the product of Preparation 432 (0.50 g, 0.84 mmol) inanhydrous N,N-dimethylformamide (20 mL) at room temperature was added1-hydroxybenzotriazole hydrate (0.126 g, 0.93 mmol) and4-methylpiperidine (0.10 mL, 0.84 mmol) This mixture stirred for 15 minat room temperature, at which time 1,3-dicyclohexylcarbodiimide (0.19 g,0.93 mmol) was added. The reaction was stirred at room temperature for15 h, at which time it was quenched with brine and extracted with ethylacetate. The combined extracts were washed with brine, dried (sodiumsulfate) and evaporated to provide a tan solid foam. The foam wasdissolved in ethyl acetate, the 1,3-dicyclohexylurea was filtered awayand the filtrate was purified by flash chromatography (silica gel, 90%ethyl acetate/hexanes—10% methanol/ethyl acetate) to give the desiredproduct as an off-white solid foam (0.24 g, 44%): ¹H NMR consistent withstructure; MS (IS) m/e 675 (M+1); Anal. Calc'd for C₃₇H₅₀N₆O₆: C, 65.85;H, 7.47; N, 12.45. Found: C, 64.70; H, 6.86; N, 12.49.

Example 236

To a stirring solution of the product of Preparation 433 (0.18 g, 0.27mmol) and anisole (0.05 mL, 0.47 mmol) in anhydrous dichloromethane (10mL) at 0° C. was added trifluoroacetic acid (2 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled, saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—5%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide the desired product as an off-white solid foam (0.12 g, 75%): ¹HNMR consistent with structure; MS (IS) m/e 573 (M−1); Anal. Calc'd forC₃₂H₄₂N₆O₄: C, 66.88; H, 7.37; N, 14.62. Found: C, 65.86; H, 7.18; N,13.82.

To a solution of the product of Preparation 433 (0.50 g, 0.84 mmol) inanhydrous N,N-dimethylformamide (20 mL) at room temperature was added1-hydroxybenzotriazole hydrate (0.13 g, 0.93 mmol) and pyrrolidine(0.07mL, 0.84 mmol). This mixture stirred for 15 min at room temperature, atwhich time 1,3-dicyclohexylcarbodiimide (0.19 g, 0.93 mmol) was added.The reaction was stirred at room temperature for 15 h, at which time itwas quenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate) and evaporatedto provide a light-brown solid foam. The foam was dissolved in ethylacetate, the 1,3-dicyclohexylurea was filtered away and the filtrate waspurified by flash chromatography (silica gel, 90% ethylacetate/hexanes—10% methanol/ethyl acetate) to give the desired productas a off-white solid foam (0.28 g, 50%): ¹H NMR consistent withstructure; MS (IS) m/e 647 (M+1); Anal. Calc'd for C₃₅H₄₆N₆O₆: C, 65.00;H, 7.17; N, 12.99. Found: C, 64.08; H, 7.31; N, 12.81.

Example 237

To a stirring solution of the product of Preparation 434 (0.20 g, 0.30mmol) and anisole (0.05 mL, 0.47 mmol) in anhydrous dichloromethane (10mL) at 0° C. was added trifluoroacetic acid (2 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled, saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—5%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide the desired product as an off-white solid foam (0.12 g, 73%): ¹HNMR consistent with structure; MS (FD) m/e 546 (M+); Anal. Calc'd forC₃₀H₃₈N₆O₄: C, 65.91; H, 7.01; N, 15.37. Found: C, 65.10; H, 7.10; N,14.97.

To a 0° C. solution of 2-ethylimidazole (10.0 g, 104 mmol) andconcentrated nitric acid (15 ml, 312 mmol) was added concentratedsulfuric acid (14 ml, 265 mmol), with stirring. After addition wascomplete, the ice bath was removed and the reaction was heated to agentle reflux for 1.5 h. The reaction was allowed to cool and was thenpoured into ice water and basified with 1N NaOH (pH˜6). The aqueousmixture was extracted with ethyl acetate and the combined extracts werewashed with brine, dried (sodium sulfate) and evaporated to provide anoff-white solid. The crude solid was recrystallized in methanol to givethe desired product as a white solid (6.26 g, 43%): ¹H NMR consistentwith structure; MS (IS) m/e 142 (M+1); Anal. Calc'd for C₅H₇N₃O₂: C,42.55; H, 5.00; N, 29.77. Found: C, 42.43; H, 4.99; N, 29.48.

To a stirring slurry of sodium hydride (01.49 g of a 60% dispersion inmineral oil, 37.2 mmol) in N,N-dimethylformamide (30 mL) at 0° C., wasadded a solution of the product of Preparation 435 (5.0 g, 35.4 mmol) inN,N-dimethylformamide (30 mL). This solution stirred at 0° C. for 10 minthen a solution of the product of Preparation 5 from Examples Part 1(9.50 g, 39.0 mmol) in N,N-dimethylformamide (30 mL) was added. Thereaction was stirred at room temperature for 15 h, at which time it wasquenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate) and evaporatedto provide a orange oil. Flash chromatography of the crude oil (silicagel, 20%-60% ethyl acetate/hexanes) yielded the desired product as alight-yellow solid (8.48 g, 79%): ¹H NMR consistent with structure; MS(IS) m/e 302 (M−1); Anal. Calc'd for C₁₅H₁₇N₃O₄: C, 59.40; H, 5.65; N,13.85. Found: C, 59.49; H, 5.43; N, 13.93.

To a suspension of 5% palladium on carbon (0.75 g) and dioxane (60 mL),in a Parr reaction bottle, was added the product of Preparation 436(0.93 g, 3.07 mmol) as a solid. The reaction bottle was placed on a Parrshaker, and shaken at room temperature for 2 h under a hydrogenatmosphere (35 psi). The reaction was filtered through a pad of Celite521 and the filtrate was then added to a previously prepared mixture ofthe product of Preparation 1d from Examples Part 2A (1.16 g, 3.07 mmol)and 1-hydroxybenzotriazole hydrate (0.46 g, 3.37 mmol) in 30 mL dioxaneat room temperature. This solution stirred for 15 min at which time1,3-dicyclohexylcarbodiimide (0.70 g, 3.37 mmol) was added. The reactionwas stirred at room temperature for 15 h, then the solvent wasevaporated under reduced pressure. The residue was dissolved in ethylacetate and the 1,3-dicyclohexylurea was filtered away. The filtrate waspurified by flash chromatography (silica gel, 50% ethylacetate/hexanes—ethyl acetate) to give the desired product as a lightorange solid foam (1.18 g, 61%): ¹H NMR consistent with structure; MS(IS) m/e 636 (M+1); Anal. Calc'd for C₃₄H₄₅N₅O_(7:) C, 64.23; H, 7.13;N, 11.02. Found: C, 63.45; H, 6.70; N, 10.91.

To a solution of the product of Preparation 437 (1.51 g, 2.38 mmol) indioxane (75 mL) and water (35 mL) at room temperature was added lithiumhydroxide (0.30 g, 7.13 mmol). The reaction stirred 25 min at roomtemperature, at which time the dioxane was evaporated under reducedpressure. The residue was diluted with water and extracted with diethylether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light tan solid foam that was used without furtherpurification (1.40 g, 97%): ¹H NMR consistent with structure; MS (IS)m/e 606 (M−1); Anal. Calc'd for C₃₂H₄₁N₅O_(7:) C, 63.25; H, 6.80; N,11.52. Found: C, 61.13; H, 6.44; N, 11.40.

To a solution of the product of Preparation 438 (0.40 g, 0.66 mmol) inanhydrous N,N-dimethylformamide (20 mL) at room temperature was added1-hydroxybenzotriazole hydrate (0.10 g, 0.72 mmol) and4-methylpiperidine (0.08 mL, 0.66 mmol). This mixture stirred for 15 minat room temperature, at which time 1,3-dicyclohexylcarbodiimide (0.15 g0.72 mmol) was added. The reaction was stirred at room temperature for15 h, at which time it was quenched with brine and extracted with ethylacetate. The combined extracts were washed with brine, dried (sodiumsulfate) and evaporated to provide a light-brown solid foam. The foamwas dissolved in ethyl acetate, the 1,3-dicyclohexylurea was filteredaway and the filtrate was purified by flash chromatography (silica gel,90% ethyl acetate/hexanes—10% methanol/ethyl acetate) to give thedesried product as a white solid foam (0.372 g, 80%): ¹H NMR consistentwith structure; MS (IS) m/e 689 (M+1); Anal. Calc'd for C₃₈H₅₂N₆O₆: C,66.26; H, 7.61; N, 12.20. Found: C, 65.31; H, 7.15; N, 11.85.

Example 238

To a stirring solution of the product of Preparation 439 (0.30 g, 0.43mmol) and anisole (0.06 mL, 0.58 mmol) in anhydrous dichloromethane (15mL) at 0° C. was added trifluoroacetic acid (3 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled, saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide the desried product as an white solid foam (0.19 g, 75%): ¹H NMRconsistent with structure; MS (FD) m/e 588 (M+); Anal. Calc'd forC₃₃H₄₄N₆O₄: C, 67.32; H, 7.53; N, 14.27. Found: C, 67.48; H, 7.32; N,14.07.

To a solution of the product of Preparation 438 (0.60 g, 1.00 mmol) inanhydrous N,N-dimethylformamide (20 mL) at room temperature was added1-hydroxybenzotriazole hydrate (0.15 g, 1.09 mmol) and pyrrolidine (0.08ml, 1.00 mmol). This mixture stirred for 15 min at room temperature, atwhich time 1,3-dicyclohexylcarbodiimide (0.23 g, 1.09 mmol) was added.The reaction was stirred at room temperature for 15 h, at which time itwas quenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate) and evaporatedto provide a tan solid foam. The foam was dissolved in ethyl acetate,the 1,3-dicyclohexylurea was filtered away and the filtrate was purifiedby flash chromatography (silica gel, 90% ethyl acetate/hexanes—10%methanol/ethyl acetate) to give the desired product as a tan solid foam(0.50 g, 76%): ¹H NMR consistent with structure; MS (IS) m/e 661 (M+1);Anal. Calc'd for C₃₄H₄₅N₅O₇: C, 65.43; H, 7.32; N, 12.72. Found: C,63.85; H, 7.03; N, 12.71.

Example 239

To a stirring solution of the product of Preparation 440 (0.35 g, 0.54mmol) and anisole (0.07 mL, 0.65 mmol) in anhydrous dichloromethane (15ML) at 0° C. was added trifluoroacetic acid (3 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled, saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide the desired product as an off-white solid foam (0.26 g, 86%): ¹HNMR consistent with structure; MS (FD) m/e 560 (M+); Anal. Calc'd forC₃₁H₄₀N₆O₄: C, 66.41; H, 7.19; N, 14.99. Found: C, 66.36; H, 7.16; N,14.78.

To a 0° C. solution of concentrated nitric acid (2.38 ml, 53 mmol) in 85mL acetic anhydride was added solid 2-phenylimidazole (7.5 g, 52 mmol),with stirring. After addition was complete, the ice bath was removed andthe reaction was heated at 95-100° C. for 0.5 h. The reaction wasallowed to cool and was then poured into ice water and neutralized with1N NaOH. The aqueous mixture was extracted with ethyl acetate and thecombined extracts were washed with brine, dried (sodium sulfate) andevaporated to provide a beige solid. The crude solid was recrystallizedin methanol to give the desired product as a off-white solid (1.55 g,16%): ¹H NMR consistent with structure; MS (IS) m/e 190 (M+1); Anal.Calc'd for C₉H₇N₃O₂: C, 57.14; H, 3.73; N, 22.21. Found: C, 57.17; H,3.85; N, 21.95.

To a stirring slurry of sodium hydride (0.30 g of a 60% dispersion inmineral oil, 7.38 mmol) in N,N-dimethylformamide (30 mL) at 0° C., wasadded a solution of the product of Preparation 441 (1.33 g, 7.03 mmol)in N,N-dimethylformamide (20 mL). This solution stirred at 0° C. for 10min then a solution of the product of Preparation 6 from Examples Part 1(1.88 g, 7.73 mmol) in N,N-dimethylformamide (20 mL) was added. Thereaction was stirred at room temperature for 15 h, at which time it wasquenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate) and evaporatedto provide a yellow oil. Flash chromatography (silica gel, 20%-50% ethylacetate/hexanes) yielded the desired product as a yellow solid (1.50 g,61%): ¹H NMR consistent with structure; MS (IS) m/e 352 (M+1); Anal.Calc'd for C₁₉H₁₇N₃O₄: C, 64.95; H, 4.88; N, 11.96. Found: C, 65.23; H,5.04; N, 11.98.

To a suspension of 5% palladium on carbon (0.68 g) and tetrahydrofuran(75 mL), in a Parr reaction bottle, was added the product of Preparation442 (1.34 g, 3.81 mmol) as a solid. The reaction bottle was placed on aParr shaker, and shaken at room temperature for 2 h under a hydrogenatmosphere (40 psi). The reaction was filtered through a pad of Celite521 and the filtrate was then added to a previously prepared mixture ofthe product of Preparation 1d from Examples Part 2A(1.45 g, 3.81 mmol)and 1-hydroxybenzotriazole hydrate (0.57 g, 4.20 mmol) in 30 mLtetrahydrofuran at room temperature. This solution stirred for 15 min atwhich time 1,3-dicyclohexylcarbodiimide (0.87 g, 4.20 mmol) was added.The reaction was stirred at room temperature for 15 h, then the solventwas evaporated under reduced pressure. The residue was dissolved inethyl acetate and the 1,3-dicyclohexylurea was filtered away. Thefiltrate was purified by flash chromatography (silica gel, 50% ethylacetate/hexanes—ethyl acetate) to give the desired product as an orangeyellow solid foam (2.04 g, 78%): ¹H NMR consistent with structure; MS(IS) m/e 684 (M+1); Anal. Calc'd for C₃₈H₄₅N₅O₇: C, 66.75; H, 6.63; N,10.24. Found: C, 65.89; H, 6.26; N, 10.12.

To a solution of the product of Preparation 443 (1.94 g, 2.84 mmol) indioxane (60 mL) and water (30 mL) at room temperature was added lithiumhydroxide (0.48 g, 1.14 mmol). The reaction stirred 25 min at roomtemperature, at which time the dioxane was evaporated under reducedpressure. The residue was diluted with water and extracted with diethylether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as an orange-yellow solid foam that was used withoutfurther purification (1.71 g, 92%): ¹H NMR consistent with structure; MS(IS) m/e 656 (M+1); Anal. Calc'd for C₃₆H₄₁N₅O₇: C, 65.94; H, 6.30; N,10.68. Found: C, 63.03; H, 5.86; N, 10.60.

To a solution of the product of Preparation 444 (0.65 g, 0.99 mmol) inanhydrous N,N-dimethylformamide (20 mL) at room temperature was added1-hydroxybenzotriazole hydrate (0.148 g, 1.09 mmol) and pyrrolidine(0.08 mL, 0.99 mmol). This mixture stirred for 15 min at roomtemperature, at which time 1,3-dicyclohexylcarbodiimide (0.23 g, 1.09mmol) was added. The reaction was stirred at room temperature for 15 h,at which time it was quenched with brine and extracted with ethylacetate. The combined extracts were washed with brine, dried (sodiumsulfate) and evaporated to provide a light-tan solid foam. The foam wasdissolved in ethyl acetate, the 1,3-dicyclohexylurea was filtered awayand the filtrate was purified by flash chromatography (silica gel, 90%ethyl acetate/hexanes—10% methanol/ethyl acetate) to give the desiredproduct as a white solid (0.31 g, 44%) ¹H NMR consistent with structure;MS (IS) m/e 709 (M+1); Anal. Calc'd for C₄₀H₄₈N₆O₆: C, 67.78; H, 6.83;N, 11.86. Found: C, 67.17; H, 6.92; N, 11.67.

Example 240

To a stirring solution of the product of Preparation 445 (0.27 g, 0.38mmol) and anisole (0.07 mL, 0.65 mmol) in anhydrous dichloromethane (10mL) at 0° C. was added trifluoroacetic acid (1.5 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled, saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide the desired product as a white solid foam (0.23 g, 99%): ¹H NMRconsistent with structure; MS (IS) m/e 609 (M+1); Anal. Calc'd forC₃₉H₄₂N₆O₈F₆: C, 55.98; H, 5.06; N, 10.04. Found: C, 56.21; H, 5.14; N,10.12.

To a stirring slurry of sodium hydride (1.12 g of a 60% dispersion inmineral oil, 28 mmol) in N,N-dimethylformamide (50 mL) at 0° C., wasadded a solution of 3-nitropyrrole (3.00 g, 27 mmol) inN,N-dimethylformamide (30 mL). This solution stirred at 0° C. for 10 minthen a solution of the product of Preparation 2 from Examples Part 2A(7.31 g, 27 mmol) in N,N-dimethylformamide (30 mL) was added. Thereaction was stirred at room temperature for 15 h, at which time it wasquenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate) and evaporatedto provide an orange-yellow oil. Flash chromatography (silica gel,30%-50% ethyl acetate/hexanes) yielded the desired product as a yellowoil (6.20 g, 75%): ¹H NMR consistent with structure; MS (IS) m/e 303(M−1); Anal. Calc'd for C₁₅H₁₆N₂O₅: C, 59.21; H, 5.30; N, 9.21. Found:C, 59.20; H, 5.40; N, 9.03.

To a suspension of 5% palladium on carbon (2.00 g) and tetrahydrofuran(100 mL), in a Parr reaction bottle, was added the product ofPreparation 446 (4.10 g, 13.5 mmol) as a solid. The reaction bottle wasplaced on a Parr shaker, and shaken at room temperature for 2 h under ahydrogen atmosphere (40 psi). The reaction was filtered through a pad ofCelite 521 and the filtrate was then added to a previously preparedmixture of the product of Preparation 1j from Examples Part 2A (5.10 g,13.5 mmol), 1,3-dicyclohexylcarbodiimide (3.06 g, 14.8 mmol) and1-hydroxybenzotriazole hydrate (2.02 g, 14.8 mmol) in 50 mLtetrahydrofuran at 0° C. The reaction was stirred for 16 h at roomtemperature, then the solvent was evaporated under reduced pressure. Theresidue was dissolved in ethyl acetate and the 1,3-dicyclohexylurea wasfiltered away. The filtrate was purified by flash chromatography (silicagel, 50% ethyl acetate/hexanes—ethyl acetate) to give the desiredproduct as a light orange solid foam (4.00 g, 47%): ¹H NMR consistentwith structure; MS (IS) m/e 635 (M+1); Anal. Calc'd for C₃₅H₄₆N₄O₇: C,66.23; H, 7.30; N, 8.83. Found: C, 66.30; H, 7.31; N, 9.03.

To a solution of the product of Preparation 447 (3.86 g, 6.08 mmol) intetrahydrofuran (60 mL) and water (30 mL) at room temperature was addedlithium hydroxide (0.64 g, 15.2 mmol). The reaction stirred 25 min atroom temperature, at which time the tetrahydrofuran was evaporated underreduced pressure. The residue was diluted with water and extracted withdiethyl ether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light tan solid foam that was used without furtherpurification (3.54 g, 96%): ¹H NMR consistent with structure; MS (IS)m/e 607 (M+1); Anal. Calc'd for C₃₃H₄₂N₄O₇: C, 65.33; H, 6.98; N, 9,23.Found: C, 64.83; H, 6.76; N, 8.65.

To a solution of the product of Preparation 448 (3.46 g, 5.71 mmol) inanhydrous dichloromethane (75 mL) at 0° C. was added N-methylmorpholine(0.76 mL, 6.86 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.11 g,6.29 mmol). This mixture stirred for 1 h, warming to room temperature,at which time 4-methylpiperidine (0.75 mL, 6.28 mmol) was added. Thereaction stirred for 2 h at room temperature, then more2-chloro-4,6-dimethoxy-1,3,5-triazine (0.20 g, 1.14 mmol) was added. Thereaction was stirred for another 1 h and the solvent was evaporatedunder reduced pressure. The residue was dissolved in ethyl acetate, thesolids were filtered away and the filtrate was purified by flashchromatography (silica gel, ethyl acetate—10% methanol/ethyl acetate) togive the desired product as an off-white solid foam (0.3.20 g, 82%): ¹HNMR consistent with structure; MS (IS) m/e 688 (M+1); Anal. Calc'd forC₃₉H₅₃N₅O₆: C, 68.10; H, 7.77; N, 10.18. Found: C, 67.55; H, 7.72; N,10.28.

Examples 241 and 242

To a stirring solution of the product of Preparation 449 (3.10 g, 4.51mmol) and anisole (0.52 mL, 4.73 mmol) in anhydrous dichloromethane (100mL) at 0° C. was added trifluoroacetic acid (12 mL) via syringe. Thereaction was stirred for 4 hours warming to room temperature and thenquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide the desired product as an off-white solid foam (2.05 g, 77%). ¹HNMR consistent with structure; MS (IS) m/e 586 (M−1); Anal. Calc'd forC₃₄H₄₅N₅O₄: C, 69.48; H, 7.72; N, 11.92. Found: C, 69.27; H, 7.69; N,11.70. Diastereomeric separation: The product was resolved by HPLC[Kromasil packing material, 15% 3A alcohol/85% heptane (w/0.2% DMEA)] toprovide two diastereomers. The first diastereomer (0.80 g) (retentiontime=7.13 min) was dissolved in ethyl acetate (20 mL) and then asaturated solution of hydrochloric acid in diethyl ether (3 mL) wasadded, with stirring. The white precipitate was collected by vacuumfiltration and rinsed with diethyl ether. Vacuum drying provided Example241 (0.79 g) as a white amorphous solid: ¹H NMR consistent withstructure; MS (IS) m/e 588 (M+1); Anal. Calc'd for C₃₄H₄₅N₅O₄.HCl: C,65.42; H, 7.42; N, 11.22. Found: C, 64.26; H, 7.37; N, 10.93. The seconddiastereomer (0.65 g) (retention time=8.23 min) was dissolved in ethylacetate (20 mL) and then a saturated solution of hydrochloric acid indiethyl ether (2 mL) was added, with stirring. The white precipitate wascollected by vacuum filtration and rinsed with diethyl ether. Vacuumdrying provided Example 242 (0.61 g) as a white amorphous solid: ¹H NMRconsistent with structure; MS (IS) m/e 588 (M+1); Anal. Calc'd forC₃₄H₄₅N₅O₄HCl: C, 65.42; H, 7.42; N, 11.22. Found: C, 64.52; H, 7.31; N,10.72.

To a 0° C. solution of pyrazole (20.0 g, 294 mmol) and fuming nitricacid (40 ml, 881 mmol) was added concentrated sulfuric acid (40 ml, 750mmol), with stirring. After addition was complete, the ice bath wasremoved and the reaction was heated to a gentle reflux for 1 h. Thereaction was allowed to cool and was then poured into ice water,providing an off-white precipitate. The precipitate was collected byvacuum filtration and the crude solid was recrystallized in methanol togive the desired product as a white solid (20.4 g, 61%): ¹H NMRconsistent with structure; MS (IS) m/e 114 (M+1).

To a stirring slurry of 2-naphthyl acetic acid in carbon tetrachloride(100 mL) at 0° C. was added thionyl chloride (64.01 g, 538 mmol). Themixture was heated at 70° C. for 1 h, then cooled to 0° C.N-bromosuccinimide (57.4 g, 323 mmol), hydrobromic acid (48% aq, 1.7 mL)and carbon tetrachloride (100 mL) were added, and this mixture washeated to reflux for 2 h. After allowing the reaction mixture to cool toroom temperature, the succinimide was filtered away and ethanol (150 mL)was added dropwise. This solution stirred for 1 h at room temperatureand was then concentrated in vacuo to provide an orange oil. The crudeoil was purified by flash chromatography (silica gel; 10% ethylacetate/hexanes) to provide a yellow oil which solidified upon sitting.The solid was triturated with 5% ethyl acetate/hexanes to provide thedesired product as a white solid (37.5 g, 48%): ¹H NMR consistent withstructure; MS (FD) m/e 292,294 (M+); Anal. Calcl'd for C₁₄H₁₃BrO₂: C,57.36; H, 4.47. Found: C, 58.27; H, 4.51.

To a stirring slurry of sodium hydride (1.30 g of a 60% dispersion inmineral oil, 32.5 mmol) in N,N-dimethylformamide (35 mL) at 0° C., wasadded a solution of the product of Preparation 451 (3.50 g, 31.0 mmol)in N,N-dimethylformamide (25 mL). This solution stirred at 0° C. for 10min then a solution of the product of Preparation 451 (9.98 g, 34.04mmol) in N,N-dimethylformamide (50 mL) was added. The reaction stirredfor 12 h at room temperature, at which time it was quenched with brineand extracted with ethyl acetate. The combined extracts were washed withbrine, dried (sodium sulfate) and evaporated in vacuo to provide ayellow oil. Flash chromatography (silica gel, 15%-40% ethylacetate/hexanes) yielded the desired product as a light-yellow oil (5.40g, 54%): ¹H NMR consistent with structure; MS (IS) m/e 326 (M+1).

To a suspension of 5% palladium on carbon (5.00 g) and tetrahydrofuran(100 mL), in a Parr reaction bottle, was added the product ofPreparation 452 (5.00 g, 15.4 mmol) as a solution in 50 mLtetrahydrofuran. The reaction bottle was placed on a Parr shaker, andshaken at room temperature for 3.5 h under a hydrogen atmosphere (35psi). The reaction was filtered through a pad of Celite 521 and thefiltrate was then added to a previously prepared mixture of the productof Preparation 1d from Examples Part 2A (4.00 g, 10.5 mmol),1,3-dicyclohexylcarbodiimide (2.44 g, 11.8 mmol) and1-hydroxybenzotriazole hydrate (1.61 g, 11.8 mmol) in 50 mLtetrahydrofuran at room temperature. The reaction was stirred for 16 hat room temperature, then the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate and the remainingsolids were filtered away. The filtrate was purified by flashchromatography (silica gel, 70% ethyl acetate/hexanes—ethyl acetate) togive the desired product as a white solid foam (4.75 g, 69%): ¹H NMRconsistent with structure; MS (IS) m/e 658 (M+1); Anal. Calc'd forC₃₆H₄₃N₅O₇: C, 65.74; H, 6.59; N, 10.65. Found: C, 65.11; H, 6.46; N,10.66.

To a solution of the product of Preparation 453 (3.95 g, 6.01 mmol) intetrahydrofuran (60 mL), water (30 mL) and ethanol (10 mL) at roomtemperature was added lithium hydroxide (1.01 g, 24.0 mmol). Thereaction stirred 25 min at room temperature, at which time thetetrahydrofuran was evaporated under reduced pressure. The residue wasdiluted with water and extracted with diethyl ether (the ether extractswere discarded). The aqueous layer was acidified (pH 2-3) with 1N HCland then extracted with diethyl ether and ethyl acetate. The combinedorganic layers were washed with brine, dried (sodium sulfate) andconcentrated under reduced pressure to provide the desired product as alight tan solid foam that was used without further purification (3.55 g,94%): ¹H NMR consistent with structure; MS (IS) m/e 630 (M+1).

To a solution of the product of Preparation 454 (0.40 g, 0.64 mmol) inanhydrous dichloromethane (20 mL) at 0° C. was added N-methylmorpholine(0.08 mL, 0.76 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.12 g,0.70 mmol). This mixture stirred for 1 h, warming to room temperature,at which time pyrrolidine (0.06 mL, 0.70 mmol) was added. The reactionstirred for 4 h at room temperature, then the solvent was evaporatedunder reduced pressure. The residue was dissolved in ethyl acetate, thesolids were filtered away and the filtrate was purified by flashchromatography (silica gel, ethyl acetate—10% methanol/ethyl acetate) togive the desired product as an off-white solid foam (0.21 g, 48%): ¹HNMR consistent with structure; MS (IS) m/e 683 (M+1); Anal. Calc'd forC₃₄H₄₆N₆O₆: C, 66.84; H, 6.79; N, 12.31. Found: C, 64.83; H, 6.53; N,12.64.

Example 243

To a stirring solution of the product of Preparation 455 (0.19 g, 0.29mmol) and anisole (0.03 mL, 0.30 mmol) in anhydrous dichloromethane (12mL) at 0° C. was added trifluoroacetic acid (1.8 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide an off-white solid foam (0.11 g, 65%). The free based materialwas dissolved in ethyl acetate (5 mL) and then a saturated solution ofhydrochloric acid in diethyl ether (1 mL) was added, with stirring. Thewhite precipitate was collected by vacuum filtration and rinsed withdiethyl ether. Vacuum drying provided the desired product (0.12 g) as awhite amorphous solid: ¹H NMR consistent with structure; MS (IS) m/e 583(M+1); Anal. Calc'd for C₃₃H₃₈N₆O₄.2HCl: C, 60.46; H, 6.15; N, 12.82.Found: C, 61.22; H, 6.50; N, 12.75.

To a solution of the product of Preparation 454 (0.50 g, 0.80 mmol) inanhydrous dichloromethane (25 mL) at 0° C. was added N-methylmorpholine(0.11 mL, 0.95 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.15 g,0.87 mmol). This mixture stirred for 1 h, warming to room temperature,at which time a 2M solution of N,N-dimethylamine (0.83 mL, 1.67 mmol)was added. The reaction stirred for 4 h at room temperature, then thesolvent was evaporated under reduced pressure. The residue was dissolvedin ethyl acetate, the solids were filtered away and the filtrate waspurified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate) to give the desired product as a light yellowsolid foam (0.27 g, 52%): ¹H NMR consistent with structure; MS (IS) m/e657 (M+1); Anal. Calc'd for C₃₆H₄₄N₆O₆: C, 65.84; H, 6.75; N, 12.80.Found: C, 63.89; H, 6.65; N, 13.06.

Example 244

To a stirring solution of the product of Preparation 456 (0.26 g, 0.40mmol) and anisole (0.04 mL, 0.42 mmol) in anhydrous dichloromethane (15mL) at 0° C. was added trifluoroacetic acid (2.3 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide an off-white solid foam (0.16 g, 64%). The free based materialwas dissolved in ethyl acetate (5 mL) and then a saturated solution ofhydrochloric acid in diethyl ether (1 mL) was added, with stirring. Thewhite precipitate was collected by vacuum filtration and rinsed withdiethyl ether. Vacuum drying provided the desired product (0.17 g) as anoff-white amorphous solid: ¹H NMR consistent with structure; MS (IS) m/e557 (M+1); Anal. Calc'd for C₃₁H₃₆N₆O₄.2HCl: C, 59.14; H, 6.08; N,13.35. Found: C, 59.87; H, 6.22; N, 13.16.

To a stirring slurry of sodium hydride (1.49 g of a 60% dispersion inmineral oil, 37.1 mmol) in N,N-dimethylformamide (35 mL) at 0° C., wasadded a solution of Preparation 450 (4.00 g, 35.4 mmol) inN,N-dimethylformamide (25 mL). This solution stirred at 0° C. for 10 minthen a solution of the product of Preparation 2 from Examples Part 2A(10.6 g, 38.9 mmol) in N,N-dimethylformamide (50 mL) was added. Thereaction stirred for 12 h at room temperature, at which time it wasquenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate) and evaporatedto provide a yellow oil. Flash chromatography (silica gel, 15%-40% ethylacetate/hexanes) yielded the desired product as a light-yellow oil (9.90g, 92%): ¹H NMR consistent with structure; MS (IS) m/e 304 (M−1); Anal.Calc'd for C₁₄H₁₅N₃O₅: C, 55.08; H, 4.95; N, 13.76. Found: C, 55.26; H,4.89; N, 13.62.

To a suspension of 5% palladium on carbon (2.50 g) and tetrahydrofuran(60 mL), in a Parr reaction bottle, was added the product of Preparation457 (2.60 g, 8.55 mmol) as a solution in 30 mL tetrahydrofuran. Thereaction bottle was placed on a Parr shaker, and shaken at roomtemperature for 3.5 h under a hydrogen atmosphere (35 psi). The reactionwas filtered through a pad of Celite 521 and the filtrate was then addedto a previously prepared mixture of the product of Preparation 1d fromExamples Part 2A (3.25 g, 8.55 mmol), 1,3-dicyclohexylcarbodiimide (1.94g, 9.40 mmol) and 1-hydroxybenzotriazole hydrate (1.28 g, 9.40 mmol) in35 mL tetrahydrofuran at room temperature. The reaction was stirred for16 h at room temperature, then the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate and the solids werefiltered away. The filtrate was purified by flash chromatography (silicagel, 70% ethyl acetate/hexanes—ethyl acetate) to give the desiredproduct as a white solid foam (4.14 g, 76%): ¹H NMR consistent withstructure; MS (IS) m/e 638 (M+1); Anal. Calc'd for C₃₃H₄₃N₅O₈: C, 62.15;H, 6.80; N, 10.98. Found: C, 62.05; H, 6.85; N, 11.07.

To a solution of the product of Preparation 458 (3.95 g, 6.21 mmol) intetrahydrofuran (60 mL), water (30 mL) and ethanol (10 mL) at roomtemperature was added lithium hydroxide (1.04 g, 24.8 mmol). Thereaction stirred 25 min at room temperature, at which time thetetrahydrofuran was evaporated under reduced pressure. The residue wasdiluted with water and extracted with diethyl ether (the ether extractswere discarded). The aqueous layer was acidified (pH 2-3) with 1N HCland then extracted with diethyl ether and ethyl acetate. The combinedorganic layers were washed with brine, dried (sodium sulfate) andconcentrated under reduced pressure to provide the desired product as anoff-white solid foam that was used without further purification (3.53 g,93%): ¹H NMR consistent with structure; MS (IS) m/e 610 (M+1); Anal.Calc'd for C₃₁H₃₉N₅O₈: C, 61.07; H, 6.45; N, 11.49. Found: C, 59.51; H,6.17; N, 11.86.

To a solution of the product of Preparation 458 (0.60 g, 0.99 mmol) inanhydrous dichloromethane (35 mL) at 0° C. was added N-methylmorpholine(0.13 mL, 1.18 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.19 g,1.09 mmol). This mixture stirred for 1 h, warming to room temperature,at which time pyrrolidine (0.09 mL, 1.04 mmol) was added. The reactionstirred for 2 h at room temperature, then the solvent was evaporatedunder reduced pressure. The residue was dissolved in ethyl acetate, thesolids were filtered away and the filtrate was purified by flashchromatography (silica gel, 90% ethyl acetate/hexanes—10% methanol/ethylacetate) to give the desired product as an off-white solid foam (0.375g, 57%): ¹H NMR consistent with structure; MS (IS) m/e 661 (M−1); Anal.Calc'd for C₃₅H₄₆N₆O₇: C, 63.43; H, 7.00; N, 12.68. Found: C, 63.03; H,7.00; N, 12.62.

Example 245

To a stirring solution of the product of Preparation 460 (0.26 g, 0.39mmol) and anisole (0.04 mL, 0.42 mmol) in anhydrous dichloromethane (15mL) at 0° C. was added trifluoroacetic acid (2.3 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide a white solid foam (0.17 g, 80%). The free based material wasdissolved in ethyl acetate (5 mL) and then a saturated solution ofhydrochloric acid in diethyl ether (1 mL) was added, with stirring. Thewhite precipitate was collected by vacuum filtration and rinsed withdiethyl ether. Vacuum drying provided the desired product (0.18 g) as awhite amorphous solid: ¹H NMR consistent with structure; MS (IS) m/e 563(M+1); Anal. Calc'd for C₃₀H₃₈N₆O₅.2HCl: C, 56.69; H, 6.34; N, 13.22.Found: C, 58.29; H, 6.29; N, 13.52.

To a solution of the product of Preparation 459 (0.60 g, 0.99 mmol) inanhydrous dichloromethane (35 mL) at 0° C. was added N-methylmorpholine(0.13 mL, 1.18 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.19 g,1.09 mmol). This mixture stirred for 1 h, warming to room temperature,at which time a 2M solution of N,N-dimethylamine (0.52 mL, 1.04 mmol)was added. The reaction stirred for 2 h at room temperature, then thesolvent was evaporated under reduced pressure. The residue was dissolvedin ethyl acetate, the solids were filtered away and the filtrate waspurified by flash chromatography (silica gel, 90% ethylacetate/hexanes—10% methanol/ethyl acetate) to give the desired productas an off-white solid foam (0.35 g, 56%): ¹H NMR consistent withstructure; MS (IS) m/e 635 (M−1); Anal. Calc'd for C₃₃H₄₄N₆O₇: C, 62.25;H, 6.97; N, 13.20. Found: C, 61.78; H, 6.89; N, 13.05.

Example 246

To a stirring solution of the product of Preparation 461 (0.25 g, 0.39mmol) and anisole (0.04 mL, 0.42 mmol) in anhydrous dichloromethane (15mL) at 0° C. was added trifluoroacetic acid (2.3 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide a white solid foam (0.19 g, 89%). The free based material wasdissolved in (5 mL) ethyl acetate and then a saturated solution ofhydrochloric acid in diethyl ether (1 mL) was added, with stirring. Thewhite precipitate was collected by vacuum filtration and rinsed withdiethyl ether. Vacuum drying provided the desired product (0.19 g) as awhite amorphous solid: ¹H NMR consistent with structure; MS (IS) m/e 537(M+1); Anal. Calc'd for C₂₈H₃₆N₆O₅.2HCl: C, 55.17; H, 6.28; N,13.79.Found: C, 56.27; H, 6.15; N, 14.06.

To a suspension of 5% palladium on carbon (0.65 g) and tetrahydrofuran(40 mL), in a Parr reaction bottle, was added the product of Preparation457 (0.65 g, 2.14 mmol) as a solution in 20 mL tetrahydrofuran. Thereaction bottle was placed on a Parr shaker, and shaken at roomtemperature for 2.5 h under a hydrogen atmosphere (35 psi). The reactionwas filtered through a pad of Celite 521 and the filtrate was then addedto a previously prepared mixture of the product of Preparation 1j fromExamples Part 2A (0.81 g, 2.14 mmol), 1,3-dicyclohexylcarbodiimide (0.49g, 2.35 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.35 mmol) in30 mL tetrahydrofuran at room temperature. The reaction was stirred for16 h at room temperature, then the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate and the solids werefiltered away. The filtrate was purified by flash chromatography (silicagel, 70% ethyl acetate/hexanes—ethyl acetate) to give the desiredproduct as a white solid foam (0.82 g, 60%): ¹H NMR consistent withstructure; MS (IS) m/e 636 (M+1); Anal. Calc'd for C₃₄H₄₅N₅O₇: C, 64.23;H, 7.13; N,11.02. Found: C, 64.53; H, 7.04; N, 10.97.

To a solution of the product of Preparation 462(0.72 g, 1.14 mmol) intetrahydrofuran (30 mL), water (15 mL) and ethanol (5 mL) at roomtemperature was added lithium hydroxide (0.19 g, 4.54 mmol). Thereaction stirred 25 min at room temperature, at which time thetetrahydrofuran was evaporated under reduced pressure. The residue wasdiluted with water and extracted with diethyl ether (the ether extractswere discarded). The aqueous layer was acidified (pH 2-3) with 1N HCland then extracted with diethyl ether and ethyl acetate. The combinedorganic layers were washed with brine, dried (sodium sulfate) andconcentrated under reduced pressure to provide the desired product as awhite solid that was used without further purification (0.71 g, 99%): ¹HNMR consistent with structure; MS (IS) m/e 606 (M−1).

To a solution of the product of Preparation 463 (0.20 g, 0.32 mmol) inanhydrous dichloromethane (20 mL) at 0° C. was added N-methylmorpholine(0.05 mL, 0.39 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.07 g,0.35 mmol). This mixture stirred for 1 h, warming to room temperature,at which time pyrrolidine (0.03 mL, 0.35 mmol) was added. The reactionstirred for 2 h at room temperature, then the solvent was evaporatedunder reduced pressure. The residue was dissolved in ethyl acetate, thesolids were filtered away and the filtrate was purified by flashchromatography (silica gel, 90% ethyl acetate/hexanes—10% methanol/ethylacetate) to give the desired product as an off-white solid foam (0.18 g,85%): ¹H NMR consistent with structure; MS (IS) m/e 661 (M+1); Anal.Calc'd for C₃₆H₄₈N₆O₆: C, 65.43; H, 7.32; N, 12.72. Found: C, 64.37; H,7.24; N, 12.47.

Example 247

To a stirring solution of the product of Preparation 464 (0.21 g, 0.31mmol) and anisole (0.04 mL, 0.42 mmol) in anhydrous dichloromethane (15mL) at 0° C. was added trifluoroacetic acid (1.8 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide a white solid foam (0.15 g, 86%). The free based material wasdissolved in ethyl acetate (5 mL) and then a saturated solution ofhydrochloric acid in diethyl ether (1 mL) was added, with stirring. Thewhite precipitate was collected by vacuum filtration and rinsed withdiethyl ether. Vacuum drying provided the desired product (0.13 g) as awhite amorphous solid: ¹H NMR consistent with structure; MS (IS) m/e 561(M+1); Anal. Calc'd for C₃₁H₄₀N₆O₄.2HCl: C, 58.76; H, 6.68; N, 13.26.Found: C, 59.73; H, 6.63; N, 13.35.

To a solution of the product of Preparation 463 (0.32 g, 0.52 mmol) inanhydrous dichloromethane (20 mL) at 0° C. was added N-methylmorpholine(0.07 mL, 0.62 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.10 g,0.57 mmol). This mixture stirred for 1 h, warming to room temperature,at which time a 2M solution of N,N-dimethylamine (0.29 mL, 0.57 mmol)was added. The reaction stirred for 2 h at room temperature, then thesolvent was evaporated under reduced pressure. The residue was dissolvedin ethyl acetate, the solids were filtered away and the filtrate waspurified by flash chromatography (silica gel, 90% ethylacetate/hexanes—10% methanol/ethyl acetate) to give the desired productas an off-white solid foam (0.19 g, 58%): ¹H NMR consistent withstructure; MS (IS) m/e 635 (M+1); Anal. Calc'd for C₃₄H₄₆N₆O₆: C, 64.33;H, 7.30; N, 13.24. Found: C, 63.64; H, 7.35; N, 12.95.

Example 248

To a stirring solution of the product of Preparation 465 (0.19 g, 0.29mmol) and anisole (0.03 mL, 0.33 mmol) in anhydrous dichloromethane (15mL) at 0° C. was added trifluoroacetic acid (1.8 mL) via syringe. Thereaction was stirred for 4 h, warming to room temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, ethyl acetate—10%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide a white solid foam (0.14 g, 88%). The free based material wasdissolved in ethyl acetate (5 mL) and then a saturated solution ofhydrochloric acid in diethyl ether (1 mL) was added, with stirring. Thewhite precipitate was collected by vacuum filtration and rinsed withdiethyl ether. Vacuum drying provided the desired product (0.12 g) as awhite amorphous solid: ¹H NMR consistent with structure; MS (IS) m/e 535(M+1); Anal. Calc'd for C₂₉H₃₈N₆O₄.2HCl: C, 57.33; H, 6.64; N, 13.83.Found: C, 58.11 H, 6.61; N, 13.78.

To a suspension of 5% palladium on carbon (2.60 g) and tetrahydrofuran(100 mL), in a Parr reaction bottle, was added the product ofPreparation 136 from Examples Part 2A (5.00 g, 15.3 mmol) as a solid.The reaction bottle was placed on a Parr shaker, and shaken at roomtemperature for 2 h under a hydrogen atmosphere (40 psi). The reactionwas filtered through a pad of Celite 521 and the filtrate was then addedto a previously prepared mixture of the product of Preparation 1j fromExamples Part 2A (5.80 g, 15.3 mmol), 1,3-dicyclohexylcarbodiimide (3.48g, 16.9 mmol) and 1-hydroxybenzotriazole hydrate (2.29 g, 16.9 mmol) in50 mL tetrahydrofuran at 0° C. The reaction was stirred for 16 h at roomtemperature, then the solvent was evaporated under reduced pressure. Theresidue was dissolved in ethyl acetate and the 1,3-dicyclohexylurea wasfiltered away. The filtrate was purified by flash chromatography (silicagel, 80% ethyl acetate/hexanes—5% methanol/ethyl acetate) to give thedesired product as a light yellow solid foam (7.96 g, 80%): ¹H NMRconsistent with structure; MS (IS) m/e 656 (M+1); Anal. Calc'd forC₃₇H₄₅N₅O₆: C, 67.77; H, 6.92; N, 10.68. Found: C, 67.49; H, 6.88; N,11.71.

To a solution of the product of Preparation 466(8.73 g, 13.3 mmol) intetrahydrofuran (120 mL) and water (60 mL) at room temperature was addedlithium hydroxide (2.23 g, 53.2 mmol). The reaction stirred 35 min atroom temperature, at which time the tetrahydrofuran was evaporated underreduced pressure. The residue was diluted with water and extracted withdiethyl ether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light yellow solid foam that was used withoutfurther purification (8.18 g, 98%): ¹H NMR consistent with structure; MS(IS) m/e 628 (M+1); Anal. Calc'd for C₃₅H₄₁N₅O₆: C, 66.97; H, 6.58; N,11.16. Found: C, 66.68; H, 6.75; N, 11.12.

To a solution of the product of Preparation 467 (2.90 g, 4.61 mmol) inanhydrous dichloromethane (40 mL) at 0° C. was added N-methylmorpholine(0.61 mL, 5.53 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.05 g,5.99 mmol). This mixture stirred for 1 h, warming to room temperature,at which time 4-methylpiperidine (0.60 mL, 5.07 mmol) was added. Thereaction stirred for 2 h at room temperature, then more2-chloro-4,6-dimethoxy-1,3,5-triazine (0.20 g) was added. The reactionwas stirred for another 1 h and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate, the solids werefiltered away and the filtrate was purified by flash chromatography(silica gel, ethyl acetate—10% methanol/ethyl acetate) to give thedesired product as a light yellow solid foam (2.99 g, 92%): ¹H NMRconsistent with structure; MS (IS) m/e 709 (M+1); Anal. Calc'd forC₄₁H₅₂N₆O₅: C, 69.47; H, 7.39; N, 11.85. Found: C, 69.30; H, 7.47; N,11.92.

Examples 249 and 250

To a stirring solution of the product of Preparation 468 (4.40 g, 6.20mmol) and anisole (0.71 mL, 6.50 mmol) in anhydrous dichloromethane (140mL) at 0° C. was added trifluoroacetic acid (14 mL) via syringe. Thereaction was stirred for 4 h warming to room temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, 5% methanol/ethylacetate—5% triethylamine/10% methanol/ethyl acetate) to provide thedesired product as a light yellow solid foam (3.75 g, 99%). ¹H NMRconsistent with structure; MS (IS) m/e 609 (M+1); Anal. Calc'd forC₃₆H₄₄N₆O₃: C, 71.03; H, 7.29; N, 13.80. Found: C, 69.83; H, 7.17; N,13.54.

Diastereomeric separation: the desired product was resolved by HPLC[Kromasil packing material, 15% 3A alcohol/85% heptane (w/0.2% DMEA)] toprovide two diastereomers. The first diastereomer (1.30 g) (retentiontime=6.77 min) was dissolved in ethyl acetate (20 mL) and then asaturated solution of hydrochloric acid in diethyl ether (3 mL) wasadded, with stirring. The white precipitate was collected by vacuumfiltration and rinsed with diethyl ether. Vacuum drying provided Example249 (1.10 g) as a white amorphous solid: ¹H NMR consistent withstructure; MS (IS) m/e 609 (M+1); Anal. Calc'd for C₃₆H₄₄N₆O₃.HCl: C,67.02; H, 7.03; N, 13.03. Found: C, 66.53; H, 6.96; N, 12.80. The seconddiastereomer (1.50 g) (retention time=9.17 min) was dissolved in ethylacetate (20 mL) and then a saturated solution of hydrochloric acid indiethyl ether (3 mL) was added, with stirring. The white precipitate wascollected by vacuum filtration and rinsed with diethyl ether. Vacuumdrying provided Example 250 (1.47 g) as a white amorphous solid: ¹H NMRconsistent with structure; MS (IS) m/e 609 (M+1); Anal. Calc'd forC₃₆H₄₄N₆O₃.HCl: C, 67.02; H, 7.03; N, 13.03. Found: C, 66.08; H, 6.95;N, 12.71.

To a solution of the product of Preparation 467 (5.10 g, 8.11 mmol) inanhydrous dichloromethane (75 mL) at 0° C. was added N-methylmorpholine(1.07 mL, 9.73 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.85 g,10.5 mmol). This mixture stirred for 1 h, warming to room temperature,at which time pyrrolidine (0.75 mL, 8.93 mmol) was added. The reactionstirred for 2 h at room temperature, then more2-chloro-4,6-dimethoxy-1,3,5-triazine (0.20 g) was added. The reactionwas stirred for another 1 h and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate, the solids werefiltered away and the filtrate was purified by flash chromatography(silica gel, ethyl acetate—10% methanol/ethyl acetate) to give thedesired product as a light yellow solid foam (5.30 g, 96%): ¹H NMRconsistent with structure; MS (IS) m/e 681 (M+1); Anal. Calc'd forC₃₉H₄₈N₆O₅: C, 68.80; H, 7.11; N, 12.34. Found: C, 68.07; H, 7.10; N,12.85.

Examples 251 and 252

To a stirring solution of the product of Preparation 469 (5.15 g, 7.55mmol) and anisole (0.86 mL, 7.93 mmol) in anhydrous dichloromethane (150mL) at 0° C. was added trifluoroacetic acid (15 mL) via syringe. Thereaction was stirred for 4 h warming to room temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, 5% methanol/ethylacetate—5% triethylamine/10% methanol/ethyl acetate) to provide thedesired product as an off-white solid foam (4.11 g, 94%). ¹H NMRconsistent with structure; MS (IS) m/e 581 (M+1); Anal. Calc'd forC₃₄H₄₀N₆O₃: C, 70.32; H, 6.94; N, 14.47. Found: C, 70.34; H, 6.79; N,13.70.

Diastereomeric separation: the desired product was resolved by HPLC[Kromasil packing material, 15% 3A alcohol/85% heptane (w/0.2% DMEA)] toprovide two diastereomers. The first diastereomer (1.70 g) (retentiontime=7.72 min) was dissolved in ethyl acetate (20 mL) and then asaturated solution of hydrochloric acid in diethyl ether (3 mL) wasadded, with stirring. The white precipitate was collected by vacuumfiltration and rinsed with diethyl ether. Vacuum drying provided Example251 (1.27 g) as a off-white amorphous solid: ¹H NMR consistent withstructure; MS (IS) m/e 581 (M+1); Anal. Calc'd for C₃₄H₄₀N₆O₃.2HCl: C,66.17; H, 6.70; N, 13.62. Found: C, 65.65; H, 6.90; N, 13.48. The seconddiastereomer (1.40 g) (retention time=10.81) was dissolved in ethylacetate (20 mL) and then a saturated solution of hydrochloric acid indiethyl ether (3 mL) was added, with stirring. The white precipitate wascollected by vacuum filtration and rinsed with diethyl ether. Vacuumdrying provided Example 252 (1.47 g) as a off-white amorphous solid: ¹HNMR consistent with structure; MS (IS) m/e 581 (M+1); Anal. Calc'd forC₃₄H₄₀N₆O₃.2HCl: C, 66.17; H, 6.70; N, 13.62. Found: C, 65.73; H, 7.03;N, 13.31.

To a suspension of 5% palladium on carbon (2.60 g) and tetrahydrofuran(100 mL), in a Parr reaction bottle, was added the product ofPreparation 99 from Examples Part 2A (5.00 g, 15.3 mmol) as a solid. Thereaction bottle was placed on a Parr shaker, and shaken at roomtemperature for 2 h under a hydrogen atmosphere (40 psi). The reactionwas filtered through a pad of Celite 521 and the filtrate was then addedto a previously prepared mixture of the product of Preparation 1j fromExamples Part 2A (5.80 g, 15.3 mmol), 1,3-dicyclohexylcarbodiimide (3.48g, 16.9 mmol) and 1-hydroxybenzotriazole hydrate (2.29 g, 16.9 mmol) in50 mL tetrahydrofuran at 0° C. The reaction was stirred for 16 h at roomtemperature, then the solvent was evaporated under reduced pressure. Theresidue was dissolved in ethyl acetate and the 1,3-dicyclohexylurea wasfiltered away. The filtrate was purified by flash chromatography (silicagel, 80% ethyl acetate/hexanes—5% methanol/ethyl acetate) to give thedesired product as a light yellow solid foam (7.96 g, 80%): ¹H NMRconsistent with structure; MS (IS) m/e 682 (M+1); Anal. Calc'd forC₃₉H₄₇N₅O₆: C, 68.70; H, 6.95; N, 10.27. Found: C, 68.27; H, 6.86; N,10.77.

To a solution of the product of Preparation 470 (8.73 g, 13.3 mmol) intetrahydrofuran (120 mL) and water (60 mL) at room temperature was addedlithium hydroxide (2.23 g, 53.2 mmol). The reaction stirred 35 min atroom temperature, at which time the tetrahydrofuran was evaporated underreduced pressure. The residue was diluted with water and extracted withdiethyl ether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light yellow solid foam that was used withoutfurther purification (8.18 g, 98%): ¹H NMR consistent with structure; MS(IS) m/e 654 (M+1); Anal. Calc'd for C₃₇H₄₃N₅O₆: C, 67.98; H, 6.63; N,10.71. Found: C, 66.83; H, 6.59; N, 10.50.

To a solution of the product of Preparation 471 (1.00 g, 1.52 mmol) inanhydrous dichloromethane (30 mL) at 0° C. was added N-methylmorpholine(0.20 mL, 1.82 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.35 g,1.98 mmol). This mixture stirred for 1 h, warming to room temperature,at which time a 2M solution of N,N-dimethylamine (0.84 mL, 1.68 mmol)was added. The reaction stirred for 2 h at room temperature, then more2-chloro-4,6-dimethoxy-1,3,5-triazine (0.08 g) was added. The reactionwas stirred for another 1 h and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate, the solids werefiltered away and the filtrate was purified by flash chromatography(silica gel, 90% ethyl acetate/hexanes—10% methanol/ethyl acetate) togive the desired product as a light yellow solid foam (0.83 g, 80%): ¹HNMR consistent with structure; MS (IS) m/e 681 (M+1); Anal. Calc'd forC₃₉H₄₈N₆O₅: C, 68.80; H, 7.11; N, 12.34. Found: C, 68.23; H, 7.03; N,12.66.

Example 253

To a stirring solution of the product of Preparation 472 (3.10 g, 4.52mmol) and anisole (0.52 mL, 4.75 mmol) in anhydrous dichloromethane (100mL) at 0°C. was added trifluoroacetic acid (10 mL) via syringe. Thereaction was stirred for 4 h warming to room temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, 5% methanol/ethylacetate—5% triethylamine/10% methanol/ethyl acetate) to provide thedesired product as an off-white solid foam (2.40 g, 91%). ¹H NMRconsistent with structure; MS (IS) m/e 581 (M+1); Anal. Calc'd forC₃₄H₄₀N₆O₃: C, 70.32; H, 6.94; N, 14.47. Found: C, 69.36; H, 6.71; N,14.10.

Diastereomeric separation: the desired product was resolved by HPLC[Kromasil packing material, 15% 3A alcohol/85% heptane (w/0.2% DMEA)] toprovide two diastereomers. The second diastereomer (0.76 g) (retentiontime=9.98 min) was dissolved in ethyl acetate (15 mL) and then asaturated solution of hydrochloric acid in diethyl ether (2 mL) wasadded, with stirring. The white precipitate was collected by vacuumfiltration and rinsed with diethyl ether. Vacuum drying provided Example253 (0.70 g) as a white amorphous solid: ¹H NMR consistent withstructure; MS (IS) m/e 581 (M+1); Anal. Calc'd for C₃₄H₄₀N₆O₃.HCl: C,66.18; H, 6.70; N, 13.62. Found: C, 64.39; H, 6.69; N, 13.19.

To a solution of the product of Preparation 5 from Examples Part 2A(3.60 g, 5.90 mmol) in anhydrous dichloromethane (60 mL) at 0° C. wasadded N-methylmorpholine (0.78 mL, 7.08 mmol) and2-chloro-4,6-dimethoxy-1,3,5-triazine (1.35 g, 7.67 mmol). This mixturestirred for 1 h, warming to room temperature, at which time a 2Msolution of N,N-dimethylamine (3.30 mL, 6.49 mmol) was added. Thereaction stirred for 2 h at room temperature, then more2-chloro-4,6-dimethoxy-1,3,5-triazine (0.30 g) was added. The reactionwas stirred for another 1 h and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate, the solids werefiltered away and the filtrate was purified by flash chromatography(silica gel, ethyl acetate—10% methanol/ethyl acetate) to give thedesired product as a light yellow solid foam (2.93 g, 78%): ¹H NMRconsistent with structure; MS (IS) m/e 637 (M+1); Anal. Calc'd forC₃₃H₄₄N₆O₇: C, 62.25; H, 6.97; N, 13.20. Found: C, 61.02; H, 6.67; N,13.72.

Example 254

To a stirring solution of the product of Preparation 473 (3.60 g, 5.65mmol) and anisole (0.65 mL, 5.93 mmol) in anhydrous dichloromethane (130mL) at 0° C. was added trifluoroacetic acid (13 mL) via syringe. Thereaction was stirred for 4 h warming to room as temperature and then wasquenched by pouring over ice-cooled saturated sodium bicarbonate. Theorganic layer was collected and the aqueous layer was extracted twicewith dichloromethane. The combined organic layers were washed withsodium bicarbonate, water and brine, then dried (sodium sulfate) andevaporated in vacuo to give an light yellow solid foam. The impure foamwas purified by flash chromatography (silica gel, 5% methanol/ethylacetate—5% triethylamine/10% methanol/ethyl acetate) to provide thedesired product as an off-white solid foam (2.20 g, 73%). ¹H NMRconsistent with structure; MS (IS) m/e 537 (M+1); Anal. Calc'd forC₂₈H₃₆N₆O₅: C, 62.67; H, 6.76; N, 15.66. Found: C, 62.53; H, 6.62; N,15.57.

Diastereomeric separation: the product was resolved by HPLC [Kromasilpacking material, 15% 3A alcohol/85% heptane (w/0.2% DMEA)] to providetwo diastereomers. The second diastereomer (0.45 g) (retentiontime=10.70 min) was dissolved in ethyl acetate (10 mL) and then asaturated solution of hydrochloric acid in diethyl ether (2 mL) wasadded, with stirring. The white precipitate was collected by vacuumfiltration and rinsed with diethyl ether. Vacuum drying provided Example254 (0.40 g) as a white amorphous solid: ¹H NMR consistent withstructure; MS (IS) m/e 537 (M+1); Anal. Calc'd for C₂₈H₃₆N₆O₅.2HCl: C,55.17; H, 6.28; N, 13.79. Found: C, 56.56; H, 6.38; N, 14.26.

To a stirring slurry of sodium hydride (0.155 g of a 60% dispersion inmineral oil, 3.86 mmol) in N,N-dimethylformamide (30 mL) at 0° C., wasadded a solution of 3-nitropyrrole (0.600 g, 3.68 mmol) inN,N-dimethylformamide (10 mL). This solution stirred at 0° C. for 10 minthen a solution of the product of Preparation 5, Examples Part 1, inN,N-dimethylformamide (10 mL) was added. The reaction was stirred atroom temperature for 15 h, at which time it was quenched with brine andextracted with ethyl acetate. The combined extracts were washed withbrine, dried (sodium sulfate) and evaporated to provide a yellow oil,which contained a 9:1 mixture of the desired regioisomer and theundesired 5-nitro-4-methyl regioisomer. Flash chromatography (silicagel, 20%-50% ethyl acetate/hexanes) yielded the desired product as alight-yellow solid (2.53 g, 60%).

To a stirring solution of the product of Preparation 474 (1.01 g, 1.59mmol) in dioxane (30 mL) and water (15 mL) at room temperature was addedlithium hydroxide (0.26 g, 6.30 mmol). The reaction stirred 25 min atroom temperature, at which time the dioxane was evaporated under reducedpressure. The residue was diluted with water and extracted with diethylether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light tan solid foam that was used without furtherpurification (0. 96 g, 99%):

To a stirring solution of Preapation 475 (0.433 g, 1.46 mmol), L-prolinemethyl ester hydrochloride (0.241 g, 1.46 mmol), 1-hydroxybenzotriazolehydrate (0.200 g, 1.46 mmol) and N,N-diisopropylethylamine (0.660 g,5.10 mmol) in anhydrous 1,2-dichlormethane (30 mL), at room temperature,was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.310 g, 1.60mmol). The reaction was stirred for 18 h at room temperature, quenchedwith water (50 mL) and the aqueous layer was extracted with ethylacetate. The combined extracts were washed with 10% citric acid,saturated sodium bicarbonate, water and brine, dried (sodium sulfate)and evaporated to provide a yellow solid. Rotary chromatography (silicagel, 35% ethyl acetate/hexanes—85% ethyl acetate/hexanes) gave 0.250 g(42%) of the desired product as a white foam solid.

To a suspension of 5% palladium on carbon (1.75 g) ethyl acetate (90 mL)and ethanol (10 mL), in a Parr reaction bottle, was added the product ofPreparation 476 (3.51 g, 11.5 mmol) as a solid. The reaction bottle wasplaced on a Parr shaker, and shaken at room temperature for 45 min undera hydrogen atmosphere (35 psi). The reaction was filtered through a padof Celite 521. The filtrate was evaporated to an orange solid foam whichwas then added to a previously prepared mixture of the product ofPreparation 1d (4.33 g, 11.5 mmol) and 1-hydroxybenzotriazole hydrate(1.72 g, 12.6 mmol) in 50 mL dioxane at room temperature. This solutionstirred for 15 min at which time 1,3-dicyclohexylcarbodiimide (1.66 g,10.3 mmol) was added. The reaction was stirred at room temperature for15 h, then the solvent was evaporated under reduced pressure. Theresidue was dissolved in ethyl acetate and the 1,3-dicyclohexylurea wasfiltered away. The filtrate was purified by flash chromatography (silicagel, 75% ethyl acetate/hexanes—10% methanol/ethyl acetate) to give thedesired product as a light tan solid foam (4.5 g, 62%):

Example 255

To a stirring solution of the product of Preparation 477 (0.77 g, 1.12mmol) and anisole (0.05 mL, 0.47 mmol) in anhydrous dichloromethane (20mL) at 0° C. was added trifluoroacetic acid via syringe. The reactionwas stirred for 4 h, warming to room temperature and then was quenchedby pouring over ice-cooled, saturated sodium bicarbonate. The organiclayer was collected and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were washed with sodiumbicarbonate, water and brine, then dried (sodium sulfate) and evaporatedin vacuo to give an light yellow solid foam. The impure foam waspurified by flash chromatography (silica gel, 100% ethyl acetate—5%methanol/95% ethyl acetate—5% triethylamine/10% methanol/85% ethylacetate) to provide the desired product as an off-white solid foam(0.625 g, 95%).

To a stirring solution of the product of Preparation 475 (0.433 g, 1.46mmol), pyrrolidine (0.241 g, 1.46 mmol), 1-hydroxybenzotriazole hydrate(0.200 g, 1.46 mmol) and N,N-diisopropylethylamine (0.660 g, 5.10 mmol)in anhydrous 1,2-dichlormethane (30 mL), at room temperature, was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.310 g, 1.60 mmol). Thereaction was stirred for 18 h at room temperature, quenched with water(50 mL) and the aqueous layer was extracted with ethyl acetate. Thecombined extracts were washed with 10% citric acid, saturated sodiumbicarbonate, water and brine, dried (sodium sulfate) and evaporated toprovide a yellow solid. Flash chromatography (silica gel, 40% ethylacetate/hexanes—100% ethyl acetate) gave 0.250 g (42%) of the desiredproduct as a white foam solid.

To a suspension of 5% palladium on carbon (1.75 g) ethyl acetate (50 mL)and ethanol (25 mL), in a Parr reaction bottle, was added Preparation478 (3.51 g, 11.5 mmol) as a solid. The reaction bottle was placed on aParr shaker, and shaken at room temperature for 45 min under a hydrogenatmosphere (35 psi). The reaction was filtered through a pad of Celite521. The filtrate was evaporated to an orange solid foam which was thenadded to a previously prepared mixture of the product of Preparation 1d(4.33 g, 11.5 mmol) and 1-hydroxybenzotriazole hydrate (1.72 g, 12.6mmol) in 50 mL dioxane at room temperature. This solution stirred for 15min at which time 1,3-dicyclohexylcarbodiimide (1.66 g, 10.3 mmol) wasadded. The reaction was stirred at room temperature for 15 h, then thesolvent was evaporated under reduced pressure. The residue was dissolvedin ethyl acetate and the 1,3-dicyclohexylurea was filtered away. Thefiltrate was purified by flash chromatography (silica gel, 50% ethylacetate/hexanes—100% ethyl acetate) to give the desired product as alight tan solid foam (4.5 g, 62%).

Example 256

To a stirring solution of the product of Preparation 479 (0.77 g, 1.12mmol) and anisole (0.05 mL, 0.47 mmol) in anhydrous dichloromethane (20mL) at 0° C. was added trifluoroacetic acid via syringe. The reactionwas stirred for 4 h, warming to room temperature and then was quenchedby pouring over ice-cooled, saturated sodium bicarbonate. The organiclayer was collected and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were washed with sodiumbicarbonate, water and brine, then dried (sodium sulfate) and evaporatedin vacuo to give an light yellow solid foam. The impure foam waspurified by flash chromatography (silica gel, 100% ethyl acetate—5%methanol/95% ethyl acetate—5% triethylamine/10% methanol/85% ethylacetate) to provide the desired product as an off-white solid foam(0.625 g, 95%).

To a stirring slurry of sodium hydride (0.155 g of a 60% dispersion inmineral oil, 3.86 mmol) in N,N-dimethylformamide (30 mL) at 0° C., wasadded a solution of 3-nitropyrrole (0.600 g, 3.68 mmol) inN,N-dimethylformamide (10 mL). This solution stirred at OoC for 10 minthen a solution of the product of Preparation 5, Examples Part 1 inN,N-dimethylformamide (10 mL) was added. The reaction was stirred atroom temperature for 15 h, at which time it was quenched with brine andextracted with ethyl acetate. The combined extracts were washed withbrine, dried (sodium sulfate) and evaporated to provide a yellow oil,which contained a 9:1 mixture of the desired regioisomer and theundesired 5-nitro-4-methyl regioisomer. Flash chromatography (silicagel, 20%-50% ethyl acetate/hexanes) yielded the desired product as alight-yellow solid (2.53 g, 60%).

To a stirring solution of the product of Preparation 480 (1.01 g, 1.59mmol) in dioxane (30 mL) and water (15 mL) at room temperature was addedlithium hydroxide (0.26 g, 6.30 mmol). The reaction stirred 25 min atroom temperature, at which time the dioxane was evaporated under reducedpressure. The residue was diluted with water and extracted with diethylether (the ether extracts were discarded) The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light tan solid foam that was used without furtherpurification (0. 96 g, 99%).

To a stirring solution of the product of Preparation 481 (0.433 g, 1.46mmol), L-proline methyl ester hydrochloride (0.241 g, 1.46 mmol),1-hydroxybenzotriazole hydrate (0.200 g, 1.46 mmol) andN,N-diisopropylethylamine (0.660 g, 5.10 mmol) in anhydrous1,2-dichlormethane (30 mL), at room temperature, was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.310 g, 1.60 mmol). Thereaction was stirred for 18 h at room temperature, quenched with water(50 mL) and the aqueous layer was extracted with ethyl acetate. Thecombined extracts were washed with 10% citric acid, saturated sodiumbicarbonate, water and brine, dried (sodium sulfate) and evaporated toprovide a yellow solid. Rotary chromatography (silica gel, 35% ethylacetate/hexanes—85% ethyl acetate/hexanes) gave 0.250 g (42%) of thedesired product as a white foam solid.

To a suspension of 5% palladium on carbon (1.75 g) methanol (25 mL), wasadded the product of Preparation 482 (3.51 g, 11.5 mmol) as a solid. Thereaction was stirred at room temperature for 3-4 h under 1 atmosphere ofH₂. The reaction was filtered through a pad of Celite 521. The filtratewas evaporated to an off-white solid foam which was then added to apreviously prepared mixture of the product of Preparation 1d (4.33 g,11.5 mmol) and 1-hydroxybenzotriazole hydrate (1.72 g, 12.6 mmol) in 50mL N,N-dimethylformamide at room temperature. This solution stirred for15 min at which time 1,3-dicyclohexylcarbodiimide (1.66 g, 10.3 mmol)was added. The reaction was stirred at room temperature for 15 h, thenquenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate), and evaporatedto give a tan solid foam. The crude foam was purified by flashchromatography (silica gel, 75% ethyl acetate/hexanes—10% methanol/ethylacetate) to provide the separated diastereomers, Preparation 483A andPreparation 483B as off-white solid foams (4.5 g, 62%).

Example 257

To a stirring solution of the product of Preparation 483A (0.77 g, 1.12mmol) and anisole (0.05 mL, 0.47 mmol) in anhydrous dichloromethane (20mL) at 0° C. was added trifluoroacetic acid via syringe. The reactionwas stirred for 4 h, warming to room temperature and then was quenchedby pouring over ice-cooled, saturated sodium bicarbonate. The organiclayer was collected and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were washed with sodiumbicarbonate, water and brine, then dried (sodium sulfate) and evaporatedin vacuo to give an light yellow solid foam. The impure foam waspurified by flash chromatography (silica gel, 100% ethyl acetate—5%methanol/95% ethyl acetate—5% triethylamine/10% methanol/85% ethylacetate) to provide the desired product as an white solid foam (0.625 g,95%).

Example 258

To a stirring solution of the product of Preparation 483B (0.77 g, 1.12mmol) and anisole (0.05 mL, 0.47 mmol) in anhydrous dichloromethane (20mL) at 0° C. was added trifluoroacetic acid via syringe. The reactionwas stirred for 4 h, warming to room temperature and then was quenchedby pouring over ice-cooled, saturated sodium bicarbonate. The organiclayer was collected and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were washed with sodiumbicarbonate, water and brine, then dried (sodium sulfate) and evaporatedin vacuo to give an light yellow solid foam. The impure foam waspurified by flash chromatography (silica gel, 100% ethyl acetate—5%methanol/95% ethyl acetate—5% triethylamine/10% methanol/85% ethylacetate) to provide the desired product as an white solid foam (0.625 g,95%).

To a stirring solution of the product of Preparation 481 (0.433 g, 1.46mmol), L-proline methyl ester hydrochloride (0.241 g, 1.46 mmol),1-hydroxybenzotriazole hydrate (0.200 g, 1.46 mmol) andN,N-diisopropylethylamine (0.660 g, 5.10 mmol) in anhydrous1,2-dichlormethane (30 mL), at room temperature, was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.310 g, 1.60 mmol). Thereaction was stirred for 18 h at room temperature, quenched with water(50 mL) and the aqueous layer was extracted with ethyl acetate. Thecombined extracts were washed with 10% citric acid, saturated sodiumbicarbonate, water and brine, dried (sodium sulfate) and evaporated toprovide a yellow solid. Rotary chromatography (silica gel, 35% ethylacetate/hexanes—85% ethyl acetate/hexanes) gave 0.250 g (42%) of thedesired product as a white foam solid.

To a suspension of 5% palladium on carbon (1.75 g) methanol (25 mL), wasadded the product of Preparation 484 (3.51 g, 11.5 mmol) as a solid. Thereaction was stirred at room temperature for 3-4 h under 1 atmosphere ofH₂. The reaction was filtered through a pad of Celite 521. The filtratewas evaporated to an off-white solid foam which was then added to apreviously prepared mixture of the product of Preparation 1d (4.33 g,11.5 mmol) and 1-hydroxybenzotriazole hydrate (1.72 g, 12.6 mmol) in 50mL N,N-dimethylformamide at room temperature. This solution stirred for15 min at which time 1,3-dicyclohexylcarbodiimide (1.66 g, 10.3 mmol)was added. The reaction was stirred at room temperature for 15 h, thenquenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate), and evaporatedto give a tan solid foam. The crude foam was purified by flashchromatography (silica gel, 75% ethyl acetate/hexanes—10% methanol/ethylacetate) to provide the desired product as an off-white solid foam (4.5g, 62%).

Example 259

To a stirring solution of the product of Preparation 485 (0.77 g, 1.12mmol) and anisole (0.05 mL, 0.47 mmol) in anhydrous dichloromethane (20mL) at 0° C. was added trifluoroacetic acid via syringe. The reactionwas stirred for 4 h, warming to room temperature and then was quenchedby pouring over ice-cooled, saturated sodium bicarbonate. The organiclayer was collected and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were washed with sodiumbicarbonate, water and brine, then dried (sodium sulfate) and evaporatedin vacuo to give an light yellow solid foam. The impure foam waspurified by flash chromatography (silica gel, 100% ethyl acetate—5%methanol/95% ethyl acetate—5% triethylamine/10% methanol/85% ethylacetate) to provide the desired product as a white solid foam (0.625 g,95%).

EXAMPLES PART 2D

To a stirring slurry of sodium hydride (0.750 g of a 60% dispersion inmineral oil, 18.7 mmol) in N-dimethylformamide (40 mL) at 0° C., wasadded a solution of 3-nitropyrrole (2.00 g, 17.8 mmol) inN,N-dimethylformamide (25 mL). This solution stirred at 0° C. for 10 minthen a solution of the product of Preparation 5 from Examples Part 1(4.77 g, 19.6 mmol) in N,N-dimethylformamide (10 mL) was added. Thereaction was stirred at room temperature for 15 h, at which time it wasquenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate) and evaporatedto provide a yellow oil. Flash chromatography (silica gel, 20%-50% ethylacetate/hexanes) yielded the desired product as a light-yellow oil (4.77g, 98%): ¹H NMR consistent with structure; MS (IS) m/e 275 (M+1).

To a stirring solution of the product of Preparation 486 (4.70 g, 17.1mmol) in dioxane (100 mL) and water (50 mL) at room temperature wasadded lithium hydroxide (2.88 g, 68.5 mmol). The reaction stirred 25 minat room temperature, at which time the dioxane was evaporated underreduced pressure. The residue was diluted with water and extracted withdiethyl ether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light tan solid foam that was used without furtherpurification (4.11 g, 98%): ¹H NMR consistent with structure; MS (IS)m/e 247 (M+1).

To a stirring solution of the product of Preparation 487 (2.50 g, 10.1mmol), L-proline methyl ester hydrochloride (2.10 g, 12.7 mmol),1-hydroxybenzotriazole hydrate (1.72 g, 12.7 mmol) andN,N-diisopropylethylamine (4.40 mL, 25.4 mmol) in anhydrousdichlormethane (90 mL), at room temperature, was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.63 g, 13.7 mmol). Thereaction was stirred for 18 h at room temperature, then was quenchedwith water and the aqueous layer was extracted with ethyl acetate. Thecombined extracts were washed with 10% citric acid, saturated sodiumbicarbonate, water and brine, dried (sodium sulfate) and evaporated toprovide a yellow solid. Flash chromatography (silica gel, 35% ethylacetate/hexanes—85% ethyl acetate/hexanes) gave 2.76 g (76%) of thedesired product as a white foam solid: ¹H NMR consistent with structure;MS (IS) m/e 358 (M+1).

To a suspension of 5% palladium on carbon (1.30 g) in ethyl acetate (90mL) and ethanol (10 mL), in a Parr reaction bottle, was added theproduct of Preparation 488 (1.30 g, 3.63 mmol) as a solid. The reactionbottle was placed on a Parr shaker, and shaken at room temperature for45 min under a hydrogen atmosphere (35 psi). The reaction was filteredthrough a pad of Celite 521. The filtrate was evaporated to an orangesolid foam which was then added to a previously prepared mixture of theproduct of Preparation 1d from Examples Part 2A (1.38 g, 3.63 mmol) and1-hydroxybenzotriazole hydrate (0.54 g, 4.00 mmol) in dioxane (50 mL) atroom temperature. This solution stirred for 15 min at which time1,3-dicyclohexylcarbodiimide (0.83 g, 4.00 mmol) was added. The reactionwas stirred at room temperature for 15 h, then the solvent wasevaporated under reduced pressure. The residue was dissolved in ethylacetate and the 1,3-dicyclohexylurea was filtered away. The filtrate waspurified by flash chromatography (silica gel, 75% ethylacetate/hexanes—10% methanol/ethyl acetate) to give the desired productas a tan solid foam (0.91 g, 40%): ¹H NMR consistent with structure; MS(IS) m/e 690 (M+1).

Example 260

To a stirring solution of the product of Preparation 489 (0.88 g, 1.28mmol) and anisole (0.15 mL, 1.28 mmol) in anhydrous dichloromethane (40mL) at 0° C. was added trifluoroacetic acid (6 mL). The reaction wasstirred for 4 h, warming to room temperature, and then was quenched bypouring over ice-cooled, saturated sodium bicarbonate. The organic layerwas collected and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were washed with sodiumbicarbonate, water and brine, then dried (sodium sulfate) and evaporatedin vacuo to give an light yellow solid foam. The impure foam waspurified by flash chromatography (silica gel, ethyl acetate—5%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide the desired product as an light yellow solid foam (0.710 g,94%): ¹H NMR consistent with structure; MS (IS) m/e 590 (M+1).

To a solution of the product of Preparation 487 (2.50 g, 10.0 mmol), inanhydrous dichloromethane (60 mL) at 0° C. was added N-methylmorpholine(1.34 mL, 12.0 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.96 g,11.0 mmol). This mixture stirred for 1 h, warming to room temperature,at which time pyrrolidine (0.93 mL, 11.0 mmol) was added. The reactionwas then stirred for an additional 2.5 h at room temperature at whichtime the solvent was evaporated under reduced pressure. The resultingresidue was dissolved in ethyl acetate and the remaining solids werefiltered away. The filtrate was purified by flash chromatography (silicagel, 40% ethyl acetate/hexanes—ethyl acetate), to provide the desiredproduct as a light yellow foam solid (2.57 g, 86%): ¹H NMR consistentwith structure; MS (IS) m/e 300 (M+1).

To a suspension of 5% palladium on carbon (0.40 g) in ethyl acetate (50mL) and ethanol (25 mL), in a Parr reaction bottle, was added theproduct of Preparation 490 (0.65 g, 2.20 mmol) as a solid. The reactionbottle was placed on a Parr shaker, and shaken at room temperature for 1h under a hydrogen atmosphere (35 psi). The reaction was filteredthrough a pad of Celite 521. The filtrate was evaporated to an orangesolid foam which was then added to a previously prepared mixture of theproduct of Preparation 1d from Examples Part 2A (0.81 g, 2.12 mmol) and1-hydroxybenzotriazole hydrate (0.31 g, 2.30 mmol) inN,N-dimethylformamide (50 mL), at room temperature. This solutionstirred for 15 min at which time 1,3-dicyclohexylcarbodiimide (0.48 g,2.30 mmol) was added. The reaction was stirred at room temperature for15 h, then was quenched with brine, and extracted with ethyl acetate.The combined extracts were washed with brine, dried (sodium sulfate),and evaporated under reduced pressure to give a brown solid foam. Theimpure solid was purified by flash chromatography (silica gel, 50% ethylacetate/hexanes—ethyl acetate) to give the desired product as a yellowsolid foam (0.46 g, 42%): ¹H NMR consistent with structure; MS (IS) m/e632 (M+1).

Example 261

To a stirring solution of the product of Preparation 491 (0.37 g, 0.59mmol) and anisole (0.03 mL, 0.30 mmol) in anhydrous dichloromethane (13mL) at 0° C. was added trifluoroacetic acid (2 mL). The reaction wasstirred for 4 h, warming to room temperature, and then was quenched bypouring over ice-cooled, saturated sodium bicarbonate. The organic layerwas collected and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were washed with sodiumbicarbonate, water and brine, then dried (sodium sulfate) and evaporatedin vacuo to give an light yellow solid foam. The impure foam waspurified by flash chromatography (silica gel, ethyl acetate—5%methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) toprovide the desired product as an light yellow solid foam (0.27 g, 86%):¹H NMR consistent with structure; MS (IS) m/e 532 (M+1); Anal. Calc'dfor C₃₀H₃₇N₅O₄: C, 67.68; H, 7.01; N, 13.17. Found: C, 67.30; H, 7.02;N, 12.80.

To a stirring slurry of sodium hydride (0.74 g of a 60% dispersion inmineral oil, 18.6 mmol) in N,N-dimethylformamide (30 mL) at 0° C., wasadded a solution of 4-nitropyrazole (2.00 g, 17.7 mmol) (fromPreparation 450) in N,N-dimethylformamide (20 mL). This solution stirredat 0° C. for 10 min then a solution of the product of Preparation 5 ofExamples Part 1 (4.75 g, 19.5 mmol) in N,N-dimethylformamide (20 mL) wasadded. The reaction was stirred at room temperature for 15 h, at whichtime it was quenched with brine and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried (sodium sulfate) andevaporated to provide a yellow oil. Flash chromatography (silica gel,20%-50% ethyl acetate/hexanes) yielded the desired product as acolorless oil (4.76 g, 97%): ¹H NMR consistent with structure; MS (IS)m/e 276 (M+1).

To a stirring solution of the product of Preparation 492 (4.65 g, 16.9mmol) in dioxane (100 mL) and water (50 mL) at room temperature wasadded lithium hydroxide (2.83 g, 67.5 mmol). The reaction stirred 25 minat room temperature, at which time the dioxane was evaporated underreduced pressure. The residue was diluted with water and extracted withdiethyl ether (the ether extracts were discarded). The aqueous layer wasacidified (pH 2-3) with 1N HCl and then extracted with diethyl ether andethyl acetate. The combined organic layers were washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to provide thedesired product as a light orange solid that was used without furtherpurification (4.09 g, 98%): ¹H NMR consistent with structure; MS (IS)m/e 248 (M+1).

To a stirring solution of the product of Preparation 493 (2.00 g, 8.09mmol), L-proline methyl ester hydrochloride (1.68 g, 10.1 mmol),1-hydroxybenzotriazole hydrate (1.38 g, 10.1 mmol) andN,N-diisopropylethylamine (3.50 mL, 20.2 mmol) in anhydrousdichlormethane (80 mL), at room temperature, was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.09 g, 10.92 mmol). Thereaction was stirred for 18 h at room temperature, then was quenchedwith water and the aqueous layer was extracted with ethyl acetate. Thecombined extracts were washed with 10% citric acid, saturated sodiumbicarbonate, water and brine, dried (sodium sulfate) and evaporated toprovide a yellow solid. Flash chromatography (silica gel, 35% ethylacetate/hexanes—85% ethyl acetate/hexanes) gave the desired product as awhite foam solid (1.80 g, 62%): ¹H NMR consistent with structure; MS(IS) m/e 359 (M+1).

To a suspension of 5% palladium on carbon (0.20 g) in methanol (25 mL),was added the product of Preparation 494 (0.36 g, 1.01 mmol) as a solid.The reaction was stirred at room temperature for 4 h under a hydrogenatmosphere (1 atm). The reaction was filtered through a pad of Celite521. The filtrate was evaporated to an off-white solid foam which wasthen added to a previously prepared mixture of the product ofPreparation 1d from Examples Part 2A (0.30 g, 0.80 mmol) and1-hydroxybenzotriazole hydrate (0.12 g, 0.88 mmol) inN,N-dimethylformamide (15 mL) at room temperature. This solution stirredfor 15 min at which time 1,3-dicyclohexylcarbodiimide (0.18 g, 0.88mmol) was added. The reaction was stirred at room temperature for 15 h,then quenched with brine and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (sodium sulfate), and evaporatedto give a tan solid foam. The crude foam was purified by flashchromatography (silica gel, 75% ethyl acetate/hexanes—10% methanol/ethylacetate) to provide the separated diastereomers, as off-white solidfoams: 495A (0.18 g, 33%) ¹H NMR consistent with structure; MS (IS) m/e691 (M+1); and 495B (0.19 g, 35%): ¹H NMR consistent with structure; MS(IS) m/e 691 (M+1).

Example 262

To a stirring solution of the product of Preparation 495A (0.15 g, 0.22mmol) in anhydrous dichloromethane (15 mL) at 0° C. was addedtrifluoroacetic acid (3 mL). The reaction was stirred for 4 h, warmingto room temperature, and then was quenched by pouring over ice-cooled,saturated sodium bicarbonate. The organic layer was collected and theaqueous layer was extracted twice with dichloromethane. The combinedorganic layers were washed with sodium bicarbonate, water and brine,then dried (sodium sulfate) and evaporated in vacuo to give an lightyellow solid foam. The impure foam was purified by flash chromatography(silica gel, ethyl acetate—5% methanol/ethyl acetate—5%triethylamine/10% methanol/ethyl acetate) to provide the desired productas a white solid foam (0.10 g, 77%): ¹H NMR consistent with structure;MS (IS) m/e 591 (M+1).

Example 263

To a stirring solution of the product of Preparation 295B (0.15 g, 0.22mmol) in anhydrous dichloromethane (15 mL) at 0° C. was addedtrifluoroacetic acid (3 mL). The reaction was stirred for 4 h, warmingto room temperature, and then was quenched by pouring over ice-cooled,saturated sodium bicarbonate. The organic layer was collected and theaqueous layer was extracted twice with dichloromethane. The combinedorganic layers were washed with sodium bicarbonate, water and brine,then dried (sodium sulfate) and evaporated in vacuo to give an lightyellow solid foam. The impure foam was purified by flash chromatography(silica gel, ethyl acetate—5% methanol/ethyl acetate—5% triethylamine/10% methanol/ethyl acetate) to provide the desired product as a whitesolid foam (0.08 g, 62%): ¹H NMR consistent with structure; MS (IS) m/e591 (M+1).

To a stirring solution of the product of Preparation 493 (0.75 g, 3.03mmol), pyrrolidine (0.32 mL, 3.79 mmol), 1-hydroxybenzotriazole hydrate(0.52 g, 379 mmol) and N,N-diisopropylethylamine (1.10 mL, 6.07 mmol) inanhydrous dichlormethane (50 mL), at room temperature, was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.79 g, 4.10 mmol). Thereaction was stirred for 18 h at room temperature, quenched with waterand the aqueous layer was extracted with ethyl acetate. The combinedextracts were washed with 10% citric acid, saturated sodium bicarbonate,water and brine, dried (sodium sulfate) and evaporated to provide ayellow solid. Flash chromatography (silica gel, 35% ethylacetate/hexanes—85% ethyl acetate/hexanes) gave the desired product as awhite foam solid (0.83 g, 91%): ¹H NMR consistent with structure; MS(IS) m/e 301 (M+1).

To a suspension of 5% palladium on carbon (0.40 g) in a mixture of ethylacetate (55 mL) and ethanol (7 mL), was added the product of Preparation496 (0.71 g, 2.35 mmol) as a solid. The reaction was shaken on a Parrshaker at room temperature for 1.5 h under a hydrogen atmosphere (35psi). The reaction was filtered through a pad of Celite 521. Thefiltrate was evaporated to an off-white solid foam which was then addedto a previously prepared mixture of the product of Preparation 1d fromExamples Part 2A (0.89 g, 2.35 mmol) and 1-hydroxybenzotriazole hydrate(0.351 g, 2.58 mmol) in N,N-dimethylformamide (35 mL) at roomtemperature. This solution stirred for 15 min at which time1,3-dicyclohexylcarbodiimide (0.53 g, 2.58 mmol) was added. The reactionwas stirred at room temperature for 15 h, then quenched with brine andextracted with ethyl acetate. The combined extracts were washed withbrine, dried (sodium sulfate), and evaporated to give a tan solid foam.The crude foam was purified by flash chromatography (silica gel, 75%ethyl acetate/hexanes—10% methanol/ethyl acetate) to provide the desriedproduct as an off-white solid foam (0.97 g, 65%): ¹H NMR consistent withstructure; MS (IS) m/e 633 (M+1).

Example 264

To a stirring solution of the product of Preparation 497 (0.75 g, 1.19mmol) and anisole (0.04 mL, 0.39 mmol) in anhydrous dichloromethane (30mL) at 0° C. was added trifluoroacetic acid (4 mL). The reaction wasstirred for 4 h, warming to room temperature, and then was quenched bypouring over ice-cooled, saturated sodium bicarbonate. The organic layerwas collected and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were washed with sodiumbicarbonate, water and brine, then dried (sodium sulfate) and evaporatedin vacuo to give a light yellow solid foam. The impure foam was purifiedby flash chromatography (silica gel, ethyl acetate—5% methanol/ethylacetate—5% triethylamine/10% methanol/ethyl acetate) to provide thedesired product as a white solid foam (0.62 g, 98%): ¹H NMR consistentwith structure; MS (IS) m/e 533 (M+1).

EXAMPLES PART 3 Preparation of 1-N-alkylated-4-nitroimidazoles

To a solution of α-bromophenylacetic acid (100 g, 466 mmol) stirring inabsolute ethanol (500 mL) at room temperature was addedp-toluenesulfonic acid monohydrate (10 g, 53 mmol) This solution washeated to reflux and, after 8 h, concentrated to dryness. The resultingresidue was dissolved in ethyl acetate, washed with saturated aqueoussodium bicarbonate, brine, dried over sodium sulfate, filtered, andconcentrated to yield 77 g (68 %) of the desired product as an orangeoil: ¹H-NMR is consistent with structure; MS (FD) 241.9, 243.9.

To a slurry of sodium hydride (13.6 g of a 60% dispersion in mineraloil, 341 mmol) stirring in N,N-dimethylformamide (240 mL) was carefullyadded 4-nitroimidazole (38.6 g, 341 mmol) such that the temperatureduring the addition was maintained below 40° C. This resulting slurrywas stirred for 1 h and then cooled to 50° C. To this mixture was slowlyadded a compound of Preparation 1 (76 g, 310 mmol) at a rate such thatthe reaction temperature was maintained below 20° C. After 4 h, thereaction was concentrated and subsequently extracted with ethyl acetate.The combined organic extracts were filtered, washed with water, brine,dried over sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel chromatography (methanol/chloroformgradient) to yield the 60.1 g (70%) of the desired product as a whitesolid: ¹H-NMR is consistent with structure; MS (FD) 275 (M+); Anal.Calc'd. for: C, 56.73; H, 4.73; N, 15.27. Found: C, 56.48; H, 4.78; N,15.08.

A solution of the product of Preparation 2 (10.00 g, 36.36 mmol) in DMF(50 mL) was added dropwise to a suspension of sodium hydride (1.60 g,40.00 mmol) in DMF (50 mL) under nitrogen at 0° C. The mixture wasstirred 10 min., then methyl iodide (2.5 mL, 40.00 mmol) was addeddropwise. The reaction was stirred thirty minutes at 0° C., then 1 h atambient temperature. The mixture was quenched with a saturated solutionof sodium bicarbonate. Ethyl acetate was added and the mixture washedwith bicarbonate followed by brine. The organic layer was dried oversodium sulfate, filtered, and concentrated in vacuo. The resulting foamwas purified by flash chromatography (300 g silica, 2:3 ethylacetate/hexanes) to yield the desired product (8.81 g, 84%) as a lightyellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal.calcd. for C₁₄H₁₅N₃O₄; 58.13; C, 5.23; H, 14.53; N, found 57.88; C,5.36; H, 14.39; N, FDMS (M+)—289.

To a solution of 4-methoxyphenylacetic acid, 98 g (590 mmol) in 300 mLof absolute ethanol was added 20 g (105 mmol) of TsOH. The reactionmixture was refluxed for 5 h then concentrated to dryness. The resultingoil was chromatographed on silica gel using 20% ethyl acetate/hexanes aseluant to afford 102 g (89%) of the desired product as a colorless oil.¹H-NMR (d, DMSO) 1.17 (t, J =8.7 Hz, 3H), 3.56 (s, 2H), 3.73 (s, 3H),4.05 (q, J=7.2 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.17 (d, 8.7 Hz, 2H); MS(ion spray) 195.3 (M+1); Anal. Calc'd for C₁₁H₁₄O₃: C, 68.02; H, 7.27.Found: C, 67.95; 7.17.

To a solution of the product of Preparation 4, 40 g (200 mmol) in 500 mLof carbon tetrachloride was added 37 g (206 mmol) of N-bromosuccinimideand 4 drops of 48% HBr. The reaction mixture was refluxed for 5 h,filtered and concentrated to dryness. The resulting oil waschromatographed on silica gel using chloroform as eluant to afford 51.1g (94%) of the desired product as a colorless oil. ¹H-NMR (d, DMSO) 1.19(t, J=8.4 Hz, 3H), 3.77 (s, 3H), 4.18 (m, 2H), 5.88 (s, 1H), 6.95 (d,J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H); MS (FD) 272, 274 (M+); Anal.Calc'd for C₁₁H₁₃BrO₃: C, 48.37; H, 4.80. Found: C, 48.52; 4.77.

To a solution of the product of Preparation 5, 49.5 g (181 mmol) in 500mL of DMF was added 20.5 g (181 mmol) of 4-nitroimidazole and 75 g (543mmol) of potassium carbonate. The reaction mixture was stirred overnightat ambient temperature, filtered and concentrated to dryness. Theresulting oil was partitioned between ethyl acetate and water andextracted with ethyl acetate. The combined organics were washed withbrine, dried over sodium sulfate, filtered and concentrated to dryness.The resulting oil was absorbed onto a silica pad and chromatographed onsilica gel using 30-70% ethyl acetates/hexanes as eluant to yield 33.6 g(61%) of the desired product as an orange oil that solidifies uponsitting. ¹H-NMR (d, DMSO) 1.17 (t, J=7.2 Hz, 3H), 3.78 (s, 3H), 4.25 (q,J=7.2 Hz, 2H), 6.57 (s, 1H), 7.02 (d, J =8.7 Hz, 2H), 7.46 (d, J=8.7 Hz,2H), 7.92 (s, 1H), 8.38 (s, 1H); MS (ion spray) 306 (M+1); Anal. Calc'dfor C₁₄H₁₅N₃O₅: C, 55.08; H, 4.95; N, 13.76. Found: C, 54.93; H, 4.89;N, 13.82

Prepared as in Preparation 3 using the product of Preparation 6 (5.00 g,16.39 mmol) in DMF (25 mL) and sodium hydride (0.72 g, 18.03 mmol) andmethyl iodide (1.12 ml, 18.03 mmol) in DMF (25 mL) to yield the desiredproduct (4.81 g, 92%) as a light yellow foam: ¹H NMR (300 MHz,CDCl₃)—consistent with structure; Anal. calcd. for C₁₅H₁₇N₃O₅; 56.42; C,5.37; H, 13.16; N; found 56.13; C, 5.35; H, 13.01; N, ISMS (M+)—320.

Biphenylacetic acid (25.2 g, 119 mmol), TsOH (3.3 g, 17 mmol), absoluteethanol (250 mL), as in Preparation 4. 25.4 g (89%) of the desiredproduct as a yellow oil. ¹H-NMR is consistent with structure; MS (FD)240.1 (M+); Anal. Calc'd for C₁₆H₁₆O₂: C, 79.97; H, 6.71. Found: C,79.75; H, 6.59.

The product of Preparation 7A (18.0 g, 75.0 mmol), N-bromosuccinimide(13.7 g, 77.25 mL), 48% HBr (4 drops), carbon tetrachloride (80 mL), asin Preparation 5 gave 22.56 g (94%) of the desired product as a yellowoil. ¹H-NMR is consistent with structure; MS (FD) 318, 320 (M+); Anal.Calc'd for C₁₆H₁₅BrO₂.0.05CHCl₃: C, 60.21; H, 4.74. Found: C, 59.50; H,4.75.

To a slurry of 2.42 g (60.5 mmol) of sodium hydride in 200 mL of DMF atambient temperature was added 6.9 g (60.5 mmol) of 4-nitroimidazole.After 10 min, 17.62 g (55.0 mmol) of the product of Preparation 8 wasadded. The resulting mixture was stirred overnight at ambienttemperature then concentrated to dryness. The residue was slurried inethyl acetate and filtered. The resulting oil was partitioned betweenethyl acetate and water and extracted with ethyl acetate. The combinedorganics were washed with brine, dried over sodium sulfate, filtered andconcentrated to dryness. The resulting oil was absorbed onto a silicapad and chromatographed on silica gel using 30-50% ethyl acetate/hexanesas eluant to yield 12.0 g (62%) of the desired product as a yellowviscous oil. ¹H-NMR is consistent with structure; MS (FD) 351 (M+).

Prepared as described in Preparation 2 using the product of Preparation9 (11.03 g, 31.39 mmol) in DMF (50 mL) and sodium hydride (1.25 g, 31.39mmol) and methyl iodide (1.9 ml, 31.39 mmol) in DMF (50 mL) to yield thedesired product (10.25 g, 89%) as a light yellow foam: ¹H NMR (300 MHz,CDCl₃)—consistent with structure; Anal. calcd. for C₂₀H₁₉N₃O₄; 65.75; C,5.26; H, 11.50; N, found 63.84; C, 5.16; H, 10.94; N, ISMS (M+)—366.

A suspension of 2-naphthyl acetic acid (49.37 g, 265.0 mmol) and thionylchloride (80 mL) in carbon tetrachloride (55 mL) was heated to refluxfor 20 minutes at which time all material went into solution. Thereaction was cooled to ambient temperature. Carbon tetrachloride (125mL), N-bromosuccinamide (56.60 g, 318.0 mmol), and hydrobromic acid (48%aq., catalytic, 0.5 mL) were added. The mixture was heated to reflux for30 min., cooled to ambient temperature, filtered, and concentrated invacuo. The material was redissolved in dichloromethane (200 mL) andexcess ethanol (100 mL) was added dropwise. The mixture was stirred atambient temperature 1 hour, then concentrated in vacuo. The crudematerial was chromatographed (700 g silica, 30% ethyl acetate/hexane) toyield a crude tan solid. This crude material was dissolveddimethylformamide (200 mL) and 4-nitroimidazole (29.78 g, 263.5 mmol)and potassium carbonate (72.70 g, 526.8 mmol) were added. The reactionwas stirred at ambient temperature, then concentrated in vacuo to 100mL. Ethyl acetate and water were added and the mixture washed withsodium bicarbonate and brine. The organic layer was dried over sodiumsulfate and concentrated in vacuo. The crude material waschromatographed (1.0 kg silica, 30% ethyl acetate/hexane) to yield thedesired product (40.2 g, 47%) as a brown foam: ¹H NMR (300 MHz,CDCl₃)—consistent with structure; Anal. calcd. for C₁₇H₁₅N₃O₄; 62.76; C,4.65; H, 12.92; N, found 60.54; C, 4.35; H, 12.04; N, ISMS (M+)—326.

Prepared as described in Preparation 3 using the product of Preparation10 (13.9 g, 42.65 mmol) in DMF (50 mL) and sodium hydride (1.71 g, 42.65mmol) and methyl iodide (2.64 ml, 42.65 mmol) in DMF (50 mL) to yieldthe desired product (10.94 g, 77%) as a light yellow oil: ¹H NMR (300MHz, CDCl₃)—consistent with structure; Anal. calcd. for C₁₈H₁₇N₃O₄;63.71; C, 5.05; H, 12.38; N, found 63.80; C, 4.98; H, 12.41; N, ISMS(M+)—340.

A solution of the product of Preparation 2 (8.35 g, 28.89 mmol) in THF(100 mL) was treated with lithium hydroxide (1.82 g, 43.34 mmol) andwater (50 mL). The reaction was stirred at ambient temperature for 30minutes. Water was added and the mixture washed with diethyl ether. ThepH of the aqueous layer was adjusted to 3.0 with 10% sodium bisulfate.The mixture was saturated with sodium chloride and washed with ethylacetate. The ethyl acetate washes were combined, dried over sodiumsulfate, filtered, and concentrated in vacuo. The resulting crude solidwas dissolved in anhydrous dichloromethane (100 mL) under nitrogen. Tothis solution was added catalytic DMF (0.1 mL) and excess oxalylchloride (25 g). This mixture was stirred 3 hours, then concentrated invacuo. The resulting crude foam was dissolved in THF (20 mL) and addeddropwise to a solution of lithium(4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone [generated by addingn-BuLi (1.6M in hexanes, 19.9 mL, 31.82 mmol) dropwise to a solution of(4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (5.64 g, 31.82 mmol) inTHF (50 mL) at −78 C. under nitrogen. This solution was stirred 20 min.,then used without further purification.]. The resulting mixture wasstirred at −78 C. for 30 min, then warmed to 0 C. The mixture wasquenched with saturated sodium bicarbonate. Ethyl acetate and water wereadded and the mixture washed with sodium bicarbonate and brine. Theorganic layer was dried over sodium sulfate, filtered, and concentratedin vacuo. The resulting foam was purified by flash chromatography (400 gsilica, 5% diethyl ether/dichloromethane) to yield diastereomer 1 (3.76g, 31% yield) and diastereomer 2 (4.32 g, 36%) of the desired product ascolorless foams: diastereomer 1—¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₂₂H₂₀N₄O₅; 62.85; C, 4.80; H, 13.33; N,found 60.97; C, 4.64; H, 12.44; N; FDMS (M+)—420: diastereomer 2—¹H NMR(300 MHz, CDCl₃)—consistent with structure; Anal. calcd. for C₂₂H₂₀N₄O₅;62.85; C, 4.80; H, 13.33; N, found 62.41; C, 4.82; H, 11.92; N; FDMS(M+)—420.

Prepared as described in Preparation 13 using the product of Preparation7 (4.80 g, 15.03 mmol) in THF (50 mL) and lithium hydroxide (1.26 g,30.06 mmol) in water (25 mL) to give the crude acid. This material wasimmediately reacted with anhydrous dichloromethane (100 mL), catalyticDMF (0.5 mL), and excess oxalyl chloride (12 mL) to give the crude acidchloride. This crude product was reacted with THF (20 mL), n-BuLi (1.6Min hexanes, 14.1 mL, 22.54 mmol), and (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (4.00 g, 22.54 mmol) in THF(50 mL) to yield diastereomer 1 (2.79 g, 41% yield) and diastereomer 2(2.80 g, 41%) of the desired product as colorless foams: diastereomer1—¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal. calcd. forC₂₃H₂₂N₄O₆; 61.33; C, 4.92; H, 12.44; N, found 60.92; C, 4.82; H, 12.03;N, ISMS (M+)—451: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₂₃H₂₂N₄O₆; 61.33; C, 4.92; H, 12.44; N, found 61.57;C, 4.98; H, 12.47; N; ISMS (M+)—451.

Prepared as in Preparation 13 using the product of Preparation 10 (10.20g, 27.92 mmol) in THF (100 mL) and lithium hydroxide (2.34 g, 55.84mmol) in water (50 mL) to give the crude acid. The resulting crude solidwas dissolved in anhydrous dichloromethane (150 mL) and reacted withcatalytic DMF (0.5 mL) and excess oxalyl chloride (23 mL). The resultingcrude foam was dissolved in THF (50 mL) and reacted with n-BuLi (1.6M inhexanes, 25.1 mL, 40.28 mmol), (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (7.14 g, 40.28 mmol), and THF(150 mL) to yield diastereomer 1 (6.21 g, 45% yield) and diastereomer 2(6.20 g, 45%) of the desired product as colorless foams: ¹H NMR (300MHz, CDCl₃)—consistent with structure; Anal. calcd. for C₂₈H₂₄N₄O₅;66.93; C, 4.99; H, 11.56; N, found 65.32; C, 5.06; H, 10.66; N, ISMS(M+)—497: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal.calcd. for C₂₈H₂₄N₄O₅; 66.93; C, 4.99; H, 11.56; N, found 65.05; C,4.92; H, 10.61; N; FDMS (M+)—497.

Prepared as in Preparation 13 using the product of Preparation 12 (10.9g, 32.27 mmol) in THF (150 mL) and lithium hydroxide (1.63 g, 38.73mmol) in water (75 mL) to give the crude acid. The resulting crude solidwas dissolved in anhydrous dichloromethane (150 mL) and reacted withcatalytic DMF (0.5 mL) and excess oxalyl chloride (23 mL). The resultingcrude foam was dissolved in THF (50 mL) and reacted with n-BuLi (1.6M inhexanes, 30.1 mL, 48.23 mmol), (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (8.55 g, 48.23 mmol), and THF(150 mL) to yield diastereomer 1 (6.13 g, 41% yield) and diastereomer 2(4.82 g, 32%) of the desired product as colorless foams: diastereomer1—¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal. calcd. forC₂₆H₂₂N₄O₅; 66.38; C, 4.71; H, 11.91; N, found 65.24; C, 4.72; H, 11.59;N, ISMS (M+)—471: diastereomer 2—¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₂₆H₂₂N₄O₅; 66.38; C, 4.71; H, 11.91; N,found 66.45; C, 4.77; H, 12.20; N, ISMS (M+)—471.

A solution of the product of Preparation 13, diastereomer 1 (2.30 g,5.48 mmol) in THF (50 mL) was added to a solution of lithium hydroxide(0.25 g, 6.03 mmol) in water (25 mL). The resulting mixture was stirredat ambient temperature for 30 minutes. Water was added and the mixturewashed with diethyl ether. The pH of the aqueous layer was adjusted to3.0 with 10% aqueous sodium bisulfate. The mixture was saturated withsodium chloride and washed with ethyl acetate. The ethyl acetate washeswere combined, dried over sodium sulfate, filtered, and concentrated invacuo. The resulting crude solid was dissolved in anhydrousdichloromethane (50 mL) under nitrogen. To this solution was addedcatalytic DMF (0.1 mL) and excess oxalyl chloride (5 g). This mixturewas stirred 3 hours, then concentrated in vacuo. The resulting crudefoam was dissolved in anhydrous dichloromethane (50 mL) and cooled to 0°C. 4-Dimethylaminopyridine (catalytic, 10 mg) and pyrrolidine (1.8 mL,18.74 mmol) were added and the resulting solution stirred for 18 hours.Dichloromethane was then added and the mixture washed with sodiumbicarbonate and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated in vacuo. The crude foam was purified byflash chromatography (silica, 100 g, 5% methanol/dichloromethane) toyield the desired product (1.73 g, 88% yield) as a colorless foam: ¹HNMR (300 MHz, CDCl₃)—consistent with structure; Anal. calcd. forC₁₆H₁₈N₄O₃; 61.14; C, 5.77; H, 17.82; N, found 60.67; C, 5.78; H, 16.03;N, FDMS (M+)—314.

Prepared as in Preparation 17 using the product of Preparation 13,diastereomer 1 (1.88 g, 5.44 mmol) in THF (50 mL) and lithium hydroxide(0.23 g, 5.63 mmol) in water (25 mL) to give the crude acid. Theresulting crude solid was dissolved in anhydrous dichloromethane (50 mL)and reacted with catalytic DMF (0.1 mL) and excess oxalyl chloride (5 g)to give the crude acid chloride. The resulting crude foam was dissolvedin anhydrous dichloromethane (50 mL) and reacted with4-Dimethylaminopyridine (catalytic, 10 mg), L-proline methyl esterhydrochloride (0.90 g, 5.44 mmol), and N,N-diisopropylethylamine (2.8mL, 16.31 mmol) to yield the desired product (1.39 g, 69% yield) as acolorless foam: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal.calcd. for C₁₈H₂₀N₄O₅; 58.60; C, 5.41; H, 15.04; N, found 57.95; C,5.40; H, 13.45; N, FDMS (M+)—372.

Prepared as in Preparation 17 using the product of Preparation 13,diastereomer 1 (1.88 g, 5.44 mmol) in THF (50 mL) and lithium hydroxide(0.23 g, 5.63 mmol) in water (25 mL) to give the crude acid. Theresulting crude solid was dissolved in anhydrous dichloromethane (50 mL)and reacted with catalytic DMF (0.1 mL) and excess oxalyl chloride (5 g)to give the crude acid chloride. The resulting crude foam was dissolvedin anhydrous dichloromethane (50 mL) and reacted with4-Dimethylaminopyridine (catalytic, 10 mg), L-proline methyl esterhydrochloride (0.90 g, 5.44 mmol), and N,N-diethylisopropylamine (2.8mL, 16.31 mmol) to yield the desired product (1.21 g, 65% yield) as acolorless foam: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal.calcd. for C₁₈H₂₂N₄O₃; 63.14; C, 6.48; H, 16.36; N, found 63.29; C,6.45; H, 15.29; N, FDMS (M+)—342.

Prepared as in Preparation 17 using the product of Preparation 14,diastereomer 1 (1.25 g, 2.78 mmol) in THF (50 mL) and lithium hydroxide(0.14 g, 3.33 mmol) in water (25 mL) to give the crude acid. Theresulting crude solid was dissolved in anhydrous dichloromethane (50 mL)and reacted with catalytic DMF (0.1 mL) and excess oxalyl chloride (5 g)to give the crude acid chloride. The resulting crude foam was dissolvedin anhydrous dichloromethane (50 mL) and reacted with4-Dimethylaminopyridine (catalytic, 10 mg) and pyrrolidine (0.24 mL,2.89 mmol) to yield the desired product (0.78 g, 86% yield) as acolorless foam: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal.calcd. for C₁₇H₂₀N₄O₄; 59.59; C, 5.85; H, 16.27; N, found 59.59; C,5.96; H, 16.19; N, ISMS (M+)—345.

Prepared as in Preparation 17 using the product of Preparation 13,diastereomer 1 (2.31 g, 5.15 mmol) in THF (50 mL) and lithium hydroxide(0.26 g, 6.18 mmol) in water (25 mL) to give the crude acid. Theresulting crude solid was dissolved in anhydrous dichloromethane (50 mL)and reacted with catalytic DMF (0.1 mL) and excess oxalyl chloride (5 g)to give the crude acid chloride. The resulting crude foam was dissolvedin anhydrous dichloromethane (50 mL) and reacted with4-Dimethylaminopyridine (catalytic, 10 mg) and dimethylamine (2.0 M inTHF, 7.7 mL, 15.46 mmol) to yield the desired product (1.57 g, 96%yield) as a colorless foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₁₅H₁₈N₄O₄; 56.60; C, 5.70; H, 17.60; N,found 57.04; C, 6.09; H, 16.82; N, ISMS (M+)—319.

Prepared as in Preparation 17 using the product of Preparation 14,diastereomer 1 (1.00 g, 2.22 mmol) in THF (50 mL) and lithium hydroxide(0.10 g, 2.44 mmol) in water (25 mL) to give the crude acid. Theresulting crude solid was dissolved in anhydrous dichloromethane (50 mL)and reacted with catalytic DMF (0.1 mL) and excess oxalyl chloride (5 g)to give the crude acid chloride. The resulting crude foam was dissolvedin anhydrous dichloromethane (50 mL) and reacted with4-Dimethylaminopyridine (catalytic, 10 mg) and 4-methylpiperidine (0.34mL, 2.71 mmol) to yield the desired product (0.38 g, 50% yield) as acolorless foam: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal.calcd. for C₁₉H₂₄N₄O₄; 61.28; C, 6.50; H, 15.05; N, found 61.38; C,6.40; H, 15.11; N, FDMS (M+)—372.

Prepared as in Preparation 17 using the product of Preparation 15,diastereomer 1 (1.00 g, 2.02 mmol) in THF (20 mL) and lithium hydroxide(0.13 g, 3.09 mmol) in water (10 mL) to give the crude acid. Theresulting crude solid was dissolved in anhydrous dichloromethane (20 mL)and reacted with catalytic DMF (0.1 mL) and excess oxalyl chloride (5g). The resulting crude foam was dissolved in anhydrous dichloromethane(20 mL) and reacted with 4-Dimethylaminopyridine (catalytic, 10 mg) andpyrrolidine (0.65 mL, 7.76 mmol) to yield the desired product (0.80 g,98% yield) as a colorless foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₂₂H₂₂N₄O₃; 67.68; C, 5.68; H, 14.34; N,found 65.36; C, 5.54; H, 13.43; N, ISMS (M+)—391.

Prepared as in Preparation 17 using the product of Preparation 15,diastereomer 1 (0.50 g, 1.00 mmol) in THF (20 mL) and lithium hydroxide(0.05 g, 1.10 mmol) in water (10 mL) to give the crude acid. Theresulting crude solid was dissolved in anhydrous dichloromethane (50 mL)and reacted with catalytic DMF (0.1 mL) and excess oxalyl chloride (5 g)to give the crude acid chloride. The resulting crude foam was dissolvedin anhydrous dichloromethane (50 mL) and reacted with4-Dimethylaminopyridine (catalytic, 10 mg), N-methylmorpholine (0.33 mL,3.00 mmol), and dimethylamine hydrochloride (0.13 g, 1.50 mmol) to yieldthe desired product (0.30 g, 82% yield) as a colorless foam: ¹H NMR (300MHz, CDCl₃)—consistent with structure; Anal. calcd. for C₂₀H₂₀N₄O₃;65.92; C, 5.53; H, 15.37; N, found 64.17; C, 5.41; H, 14.15; N, ISMS(M+)—365.

Prepared as in Preparation 17 using the product of Preparation 15,diastereomer 1 (0.40 g, 0.80 mmol) in THF (20 mL) and lithium hydroxide(0.04 g, 0.96 mmol) in water (10 mL) to give the crude acid. Theresulting crude solid was dissolved in anhydrous dichloromethane (50 mL)and reacted with catalytic DMF (0.1 mL) and excess oxalyl chloride (5 g)to give the crude acid chloride. The resulting crude foam was dissolvedin anhydrous dichloromethane (50 mL) and reacted with4-Dimethylaminopyridine (catalytic, 10 mg) and 4-methylpiperidine (0.24mL, 2.89 mmol) to yield the desired product (0.30 g, 90% yield) as acolorless foam: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal.calcd. for C₂₄H₂₆N₄O₃; 68.88; C, 6.26; H, 13.39; N, found 67.40; C,6.72; H, 12.45; N, FDMS (M+)—419.

Prepared as in Preparation 17 using the product of Preparation 16,diastereomer 1 (1.00 g, 2.13 mmol) in THF (20 mL) and lithium hydroxide(0.10 g, 2.33 mmol) in water (10 mL) to give the crude acid.

The resulting crude solid was dissolved in anhydrous dichloromethane (20mL) and reacted with catalytic DMF (0.1 mL) and excess oxalyl chloride(5 g). The resulting crude foam was dissolved in anhydrousdichloromethane (20 mL) and reacted with 4-Dimethylaminopyridine(catalytic, 10 mg) and pyrrolidine (0.61 mL, 6.39 mmol) to yield thedesired product (0.42 g, 54% yield) as a colorless foam: ¹H NMR (300MHz, CDCl₃)—consistent with structure; Anal. calcd. for C₂₀H₂₀N₄O₃;65.92; C, 5.53; H, 15.38; N, found 61.50; C, 5.41; H, 13.91; N, ISMS(M+)—365.

Preparation of Dipeptide Acids

To a solution of boc-(OBz)-D-Ser-OH (25.0 g, 84.7 mmol) stirring inanhydrous N,N-dimethylformamide (500 mL) at room temperature was addedsodium bicarbonate (14.2 g, 169 mmol) followed by methyl iodide (26.4mL, 424 mmol). After 18 h, the reaction mixture was concentrated toapproximately 100 mL. Ethyl acetate was added and the mixture washedwith aqueous sodium bicarbonate and brine. The organic extract was driedand concentrated to give the desired compound (25 g, 96%) as a lightyellow oil: ¹H NMR (300 MHz, CDCl₃) d 1.45 (s, 9H), 3.70 (m, 1H), 3.75(s, 3H), 3.85 (m, 1H), 4.50 (m, 3H), 7.30 (m, 5H); MS (FD) m/e 310;Anal. calc'd for C₁₆H₂₃NO₅: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.31;H, 7.49; N, 4.43.

To a solution of the product of Preparation 27 (5.0 g, 16 mmol) stirringin dichloromethane (40 mL) and anisole (1 mL) at 0° C. was addedtrifluoroacetic acid (10 mL). After 4 h at room temperature, saturatedsodium bicarbonate solution was added and the mixture extracted withethyl acetate. The combined organic extracts were washed with brine,dried over sodium sufate, and concentrated. The crude product was usedin the next step without further purification.

To a solution of the product of Preparation 28 (65.4 mmol),boc-a-aminoisobutyric acid (13.2 g, 65.4 mmol), 1-hydroxybenzotriazole(8.8 g, 65.4 mmol), and N,N-diisopropylethylamine (22.8 mL, 130.7 mmol)stirring in dichloromethane (500 mL) at 0° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (12.3 g, 71.9 mmol). After18 h, ethyl acetate and saturated ammonium chloride were added and themixture extracted with ammonium chloride, sodium bicarbonate, and brine.The organic extracts were dried over sodium sulfate and concentrated.Purification by silica gel chromatography (25% ethyl acetate/hexanes)yielded the desired compound (21.6 g, 83%) as a white solid: ¹H NMR (300MHz, CDCl₃) d 1.39 (S, 9H), 48 (s, 6H), 3.62 (dd, J=3.4, 9.1 Hz, 1H),3.70 (s, 3H), 3.85 (dd, J=3.4, 9.1 Hz, 1H), 4.48 (dd, J=12.5, 22.7 Hz,2H), 4.75 (m, 1H), 4.92 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.35 (m, 5H);MS (FD) m/e 395; Anal. calc'd for C₂₀H₃₀N₂O₆: C, 60.90; H, 7.67; N,7.10. Found: C, 61.02; H, 7.78; N, 7.10.

To a solution of the product of Preparation 29 (5.30 g, 13.4) stirringin dioxane (100 mL)/water (50 mL) at room temperature was added lithiumhydroxide (2.80 g, 67.3 mmol). After 18 h, water was added and thesolution concentrated. The resulting mixture was extracted with diethylether. Sodium chloride was added to the aqueous layer and the pHadjusted to 3.5 with 1 N HCl. The resulting mixture was extracted withethyl acetate and the combined organic extracts dried over sodiumsulfate then concentrated to yield the title compound (4.40 g, 86%) as awhite foam: ¹H NMR (300 MHz, CDCl₃) d 1.39 (s, 9H), 1.45 (s, 3H), 1.47(s, 3H), 3.68 (m, 1H), 3.95 (m, 1H), 4.54 (s, 2H), 4.70 (m, 1H), 5.51(bs, 1H), 7.18 (d, J=9.1 Hz, 1H), 7.25 (m, 5H), 9.90 (bs, 1H); MS (FD)m/e 381; Anal. calc'd for C₁₉H₂₈N₂O₆: C, 59.99; H, 7.42; N, 7.36. Found:C, 59.74; H, 7.26; N, 7.30.

A solution of sodium ethoxide was generated by the addition of sodiummetal (52.89 grams, 2.3007 mol) over 3 hours to ethanol (1500 mL). Tothe sodium ethoxide solution at ambient temperature was added a solutionof diethylacetamidomalonate (499.75 grams, 2.3007 mol) dissolved inethanol (225 mL). The reaction mixture was stirred for 1.5 hours atambient temperature. 1-bromo-3-phenylpropane (458.07 grams, 2.3007 mol)was added over 15 minutes and the reaction mixture was refluxed untilcomplete as determined by hplc (16 hours). The reaction mixture wasconcentrated to dryness and the residue partitioned between ethylacetate (1×1500 mL and 2×500 mL) and water (1500 mL). The ethyl acetatelayers were combined, washed with saturated sodium chloride solution(4×500 mL), dried using sodium sulfate, and concentrated to give 752.1grams (98%) of the desired product as a light yellow solid. A 1.0 gramsample was recrystallized from hexane:ethyl acetate (19:1, v:v) to givea mp 84-86° C. ¹H nmr (CDCl₃): δ1.18-1.23 (t, 6H), 1.37-1.50 (m, 2H),2.02 (s, 3H), 2.34-2.41 (m, 2H), 2.58-2.62 (t, 2H), 4.16-4.24 (q, 4H),6.76 (s, broad, 1H), 7.11-7.28 (m, 5H). ¹³C nmr (CDCl₃): δ13.95, 23.03,25.67, 31.85, 35.45, 62.46, 66.49, 125.40, 125.90, 128.27, 128.35,141.77, 168.11, 168.94. MS (FIA) m/z 336.3 ([M+H]⁺). IR (KBr, cm⁻¹)1645.98 (amide), 1744.76 (C═O). Anal. Calcd. for C₁₈H₂₅NO₅: C, 64.46; H,7.51; N, 4.17. Found: C, 64.60; H, 7.37; N, 4.39.

A slurry consisting of the product from Preparation 31 (249.15 grams,0.7428 mol) and 2.5 N sodium hydroxide solution was heated at 100° C.for three hours. The reaction mixture was cooled to 30° C. and the pHadjusted to 5.0 using concentrated hydrochloric acid. The solution washeated to 100° C. and the pH was held at 5.0 using concentratedhydrochloric acid as needed until the reaction was complete asdetermined by hplc. The solution was filtered while hot throughdiatomaceous earth. The filtrate was cooled to 5-10° C. and the pHadjusted to 1.0 using concentrated hydrochloric acid. The resultingslurry was stirred for 1 hour at 5° C., filtered, and dried in vacuum at50° C. to give 160.34 grams (92%) of(DL)-N-acetyl-2-amino-5-phenylpentanoic acid as a white powder, mp145-148° C. ¹H nmr (DMSO-d₆): δ1.60-1.71 (m, 4H), 1.86 (s, 3H),2.56-2.59 (m, 2H), 4.19-4.23 (m, 1H), 7.16-7.30 (m, 5H), 8.14 (d, 1H).¹³C nmr (DMSO-d₆): δ23.17, 28.25, 31.55, 35.51, 52.55, 126.60, 129.14,142.64, 170.25, 174.65. MS (FIA) m/z 236.2 (M⁺). IR (KBr, cm⁻¹) 1609.17(amide), 1741.12 (C═O). Anal. Calcd. for C₁₃H₁₇NO₃: C, 66.36; H, 7.28;N, 5.95. Found: C, 66.41; H, 7.15; N, 5.96.

A solution consisting of (DL)-N-acetyl-2-amino-5-phenylpentanoic acid(438.0 grams, 1.862 mol), cobalt chloride (1.10 grams), 2N potassiumhydroxide solution (931 mL, 1.862 mol), and water (8000 mL) was adjustedto a pH of 8.0 by the addition of 2N potassium hydroxide solution. Tothe reaction mixture was added Acylase I (Aspergillus melleus, 39.42grams) and vigorously stirred for 24 hours at 40° C. while maintaining apH of 8.0 by addition of 2N potassium hydroxide. The resulting slurrywas filtered. The filtrate was adjusted to a pH of 2.0 giving a thickslurry. The product was isolated by filtration, washed with hexane (2000mL) and dried in vacuum at 50° C. to give 188.52 grams (43%) of(D)-N-acetyl-2-amino-5-phenylpentanoic acid. ¹H nmr (DMSO-d₆):δ1.59-1.74 (m, 4H), 1.86 (s, 3H), 2.57-2.60 (m, 2H), 4.22-4.26 (m, 1H),7.16-7.30 (m, 5H), 8.02 (d, 1H), 12.39 (s, broad, 1H). ¹³C nmr(DMSO-d₆): δ23.18, 28.13, 31.66, 35.54, 52.58, 126.56, 129.10, 142.67,170.12, 174.48. MS (FIA) m/z 236.1 (M⁺). IR (KBr, cm⁻¹) 1625.08 (amide),1700.24 (C═O). Anal. Calcd. for C₁₃H₁₇NO₃: C, 66.36; H, 7.28; N, 5.95.Found: C, 66.49; H, 7.00; N, 6.03.

A solution consisting of (D)-N-acetyl-2-amino-5-phenylpentanoic acid(188.8 grams, 0.8024 mol), ethanol (535 mL), and concentratedhydrochloric acid (268 mL, 3.21 mol) was warmed to 85° C. and monitoredby hplc. The reaction was determined to be incomplete by hplc at 14.5hours and additional concentrated hydrochloric acid (50 mL) was added.The reaction was determined to be complete by hplc after 22.5 hours.Water was azeotropically distilled from the reaction by continuousaddition and distillation of 8000 mL of ethanol. The ethanol wasazeotropically distilled from the reaction by the continuous additionand distillation of ethyl acetate (2000 mL). Upon cooling the solutionto 0° C. the product crystallized. The solution containing the productwas stirred for 1 hour at 0° C., filtered, and the cake dried in vacuumat 40° C. to give 199.0 grams (96%) of 2-amino-5-phenylpentanoic acid,ethyl ester hydrochloride, mp 117-121° C. ¹H nmr (DMSO-d₆): δ1.15-1.21(t, 3H), 1.50-1.89 (m, 4H), 2.48-2.67 (m, 2H), 3.92-3.98 (t, 1H),4.08-4.25 (m, 2H), 7.12-7.29 (m, 5H), 8.76 (s, broad, 3H). ¹³C nmr(DMSO-d₆): δ13.90, 25.97, 29.52, 34.41, 51.71, 61.56, 124.91, 125.81,128.24, 141.27, 169.35. MS (FIA) m/z 222.3 (M⁺). IR (KBr, cm⁻¹) 1741.14(C═O). [α]²⁰ _(D)=−11.17(c=30.62 mg/3 mL, MeOH). Anal. Calcd. forC₁₃H₂₀NO₂Cl: C, 60.58; H, 7.82; N, 5.43. Found: C, 60.45; H, 7.67; N,5.55.

A slurry consisting of N-t-BOC-α-aminoisobutyric acid (90.64 grams,0.446 mol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (75.90 grams, 0.425mol), N-methyl morpholine (88.13 grams, 0.871 mol), and diethyl ether(1000 mL) was stirred at ambient temperature until complete asdetermined by hplc (3 hours). The 2-amino-5-phenylpentanoic acid, ethylester hydrochloride (109.55 grams, 0.425 mol) was added and the reactionmixture stirred for 16 hours at ambient temperature. The reactionmixture was partitioned between 10% citric acid solution (1000 mL) andethyl acetate (3×500 mL). The organic phase was washed with 10% citricacid solution (3×500 mL), saturated sodium bicarbonate solution (3×500mL), water (1×500 mL), dried using sodium sulfate, and concentrated todryness. The residue was recrystallized from hexane (3000 mL) to give155.11 grams of compound 2, mp 97-99° C. ¹H nmr (CDCL₃): δ1.25-1.28 (t,3H), 1.43 (s, 9H), 1.48 (s, 3H), 1.50 (s, 3H), 1.70-1.73 (m, 3H),1.87-1.93 (m, 1H), 2.62-2.67 (m, 2H), 4.16-4.21 (m, 2H), 4.57-4.62 (m,1H), 4.95 (s, 1H), 6.96 (s, broad, 1H), 7.16-7.19 (m, 3H), 7.26-7.33 (m,2H). ¹³C nmr (CDCl₃): δ14.53, 26.32, 27.17, 28.67, 32.47, 35.73, 52.54,57.17, 61.62, 126.21, 128.69, 128.79, 142.12, 154.99, 172.81, 174.69. MS(FIA) m/z 407.5 ([M+H]⁺). IR (KBr, cm⁻¹) 1652.75, 1685.52 (amides),1741.73 (C═O). [α]²⁰ _(D)=7.83 (c=10.22 mg/1 mL, MeOH). UV (0.1%trifluoroacetic acid in water: acetonitrile) λ_(max) 215.6 nm. Anal.Calcd. for C₂₂H₃₄N₂O₅: C, 65.00; H, 8.43; N, 6.89. Found: C, 65.23; H,8.34; N, 6.94.

A solution consisting of the product of Preparation 35 (152.53 grams,0.3752 mol) and tetrahydrofuran (884 mL) was cooled to 5° C. A solutionconsisting of lithium hydroxide (26.96 grams, 1.126 mol) and water (1419mL) was added to the reaction dropwise over 10 minutes maintaining atemperature of 5-10° C. Ethanol (183 mL) was added and the reactionstirred at 5-10 ° C. until complete as determined by hplc (2 hours). ThepH of the reaction mixture was adjusted to 2.0 using 6 N hydrochloricacid solution while maintaining 5-10° C. The product was extracted fromsolution with ethyl acetate (3×500 mL). The ethyl acetate extracts werecombined, dried using sodium sulfate, and concentrated to dryness togive 141.51 grams (100%) of 427623. ¹H nmr (DMSO-d₆): δ1.32-1.37 (m,15H), 1.57-1.75 (m, 4H), 2.51-2.58 (m, 2H), 4.23-4.27 (m, 1H), 6.85 (s,broad, 1H), 7.15-7.28 (m, 5H), 7.42 (d, 1H), 12.5 (s, broad, 1H). ¹³Cnmr (DMSO-d₆): δ26.31, 27.85, 29.00, 31.86, 35.60, 52.53, 56.60, 78.95,126.52, 129.05, 129.10, 142.69, 155.06, 174.40, 175.17. MS (FIA) m/z379.5 ([M+H]⁺). IR (KBr, cm³¹ ¹) 1641.98, 1692.22 (amides), 1719.72(C═O). [α]²⁰ _(D)=−5.73 (c=10.48 mg/1 mL, MeOH).

Anal. Calcd. for C₂₀H₃₀N₂O₅: C, 63.47; H, 7.99; N, 7.40. Found: C,63.25; H, 7.84; N, 7.46.

N-Methyl morpholine (4.79 mL, 2 eq, 47.3 mm) was added to a stirredslurry of N-Boc-a-aminoisobutyric acid (4.43 g, 21.7 mm, 1 eq) and 3.89g (21.7 mm, 1.0 eq) of 2-chloro-(4,6)-dimethoxy-1,3,5-triazine (CDMT) in100 mL of diethyl ether. After stirring the reaction mixture at ambienttemperature for 1.5 hours, D-tryptophan ester hydrochloride was added.After stirring overnight, the reaction mixture was quenched by theaddition of 150 mL of 10% aqueous citric acid solution. The layers wereseparated and the ether layer was washed with 50 mL of saturated sodiumbicarbonate solution and 50 mL of water. Lithium hydroxide (2.43 g, 5eq) was dissolved in 100 ml of water and the solution was added to thediethyl ether solution and stirred vigorously for 4 hours at roomtemperature. The layers were separated and the pH of the aqueous layerswas adjusted to 5.6 with 1M HCl. The pH was then adjusted to 3.95 with10% citric acid solution and the aqueous layer was extracted with 100 mLof ethyl acetate. The ethyl acetate layers were washed with brine, driedover magnesium sulfate and filtered. The volatiles were removed undervacuum to give 82% yield of the desired product as a white foam. 1H-NMRconsistent with structure.

Coupling of Dipeptide Acids to Nitroimidazoles

A solution of the product of Preparation 17 (1.66 g, 5.29 mmol) in THF(5 mL) was added to a suspension of 5% palladium on carbon (0.80 g,catalytic, 25 mL THF) under inert atmosphere. The resulting mixture wasplaced under hydrogen (40 psi) on a Parr shaker for 1.5 hours. Theresulting mixture was placed under nitrogen and celite added. Themixture was then filtered and rinsed with THF. The filtrate was placeunder nitrogen and HOBT (0.71 g, 5.29 mmol), the product of Preparation30 (2.01 g, 5.29 mmol), EDC (1.00 g, 5.81 mmol), and DIEA (1.0 mL, 5.81mmol) were added. The resulting mixture was stirred 18 hours at ambienttemperature, then concentrated in vacuo. The crude material wasdissolved in ethyl acetate and washed with sodium bicarbonate and brine.The organic layer was dried over sodium sulfate, filtered, andconcentrated in vacuo. The resulting crude foam was purified by flashchromatography (silica, 100 g, 2% methanol/dichloromethane) to yield thedesired product (0.66 g, 19% yield) as a light yellow foam: ¹H NMR (300MHz, CDCl₃)—consistent with structure; Anal. calcd. for C₃₅H₄₆N₆O₆;65.00; C, 7.17; H, 12.99; N, found 63.21; C, 6.92; H, 12.54; N, FDMS(M+)—646.

Prepared as in Preparation 38 using the product of Preparation 18 (1.39g, 3.74 mmol) and 5% palladium on carbon (0.70 g, catalytic, 25 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.50 g, 3.74 mmol) , the product of Preparation 30 (1.42 g, 3.74 mmol),diisopropylethylamine (0.65 mL, 3.74 mmol), and EDCI (0.71 g, 4.11 mmol)to yield the desired product (0.86 g, 33% yield) as a light yellow foam:¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal. calcd. forC₃₇H₄₈O₈N₆; 63.05; C, 6.86; H, 11.92; N, found 63.01; C, 6.64; H, 11.85;N, FDMS (M+)—705.

Prepared as in Preparation 38 using the product of Preparation 19 (1.21g, 3.53 mmol) and 5% palladium on carbon (0.80 g, catalytic, 25 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.48 g, 3.53 mmol), the product of Preparation 30 (1.34 g, 3.53 mmol),diisopropylethylamine (0.6 mL, 3.53 mmol), and EDCI (0.67 g, 3.88 mmol)to yield the desired product (0.97 g, 41% yield) as a light yellow foam:¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal. calcd. forC₃₇H₅₀N₆O₆; 65.85; C, 7.47; H, 12.45; N, found 64.96; C, 7.48; H, 12.04;FDMS (M+)—675.

Prepared as in Preparation 38 using the product of Preparation 20 (0.77g, 2.24 mmol) and 5% palladium on carbon (0.80 g, catalytic, 25 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.30 g, 2.46 mmol), the product of Preparation 36 (0.85 g, 2.24 mmol),and DCC (0.51 g, 2.46 mmol) to yield the desired product (0.70 g, 46%yield) as a light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₃₇H₅₀N₆O₆; 65.85; C, 7.47; H, 12.45; N,found 65.83; C, 7.27; H, 12.38; N, ISMS (M+)—675.

Prepared as in Preparation 38 using the product of Preparation 22 (0.92g, 2.47 mmol) and 5% palladium on carbon (1.00 g, catalytic, 30 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.35 g, 2.47 mmol), the product of Preparation 36 (0.94 g, 2.47 mmol),and DCC (0.56 g, 2.72 mmol) to yield the desired product (0.92 g, 53%yield) as a light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₃₉H₅₄N₆O₆; 66.64; C, 7.74; H, 11.96; N,found 66.65; C, 7.65; H, 12.02; N, ISMS (M+)—702.

Prepared as in Preparation 38 using the product of Preparation 22 (1.32g, 3.55 mmol) and 5% palladium on carbon (1.4 g, catalytic, 50 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.48 g, 3.55 mmol), the product of Preparation 30 (1.35 g, 3.55 mmol),and DCC (0.81 g, 3.91 mmol) to yield the desired product (0.82 g, 33%yield) as a light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₃₈H₅₂N₆O₇; 64.75; C, 7.44; H, 11.92; N,found 66.19; C, 7.17; H, 12.10; N, ISMS (M+)—705.

Prepared as in Preparation 38 using the product of Preparation 21 (0.27g, 0.85 mmol) and 5% palladium on carbon (0.30 g, catalytic, 20 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.11 g, 0.85 mmol), the product of Preparation 36 (0.32 g, 0.85 mmol),N-methylmorpholine (0.10 mL, 0.85 mmol), and EDCI (0.16 g, 0.93 mmol) toyield the desired product (0.70 g, 46% yield) as a light yellow foam: ¹HNMR (300 MHz, CDCl₃)—consistent with structure; Anal. calcd. forC₃₅H₄₈N₆O₆; 66.43; C, 7.65; H, 13.28; N, found 63.53; C, 6.83; H, 12.38;N, ISMS (M+)—649.

Prepared as in Preparation 38 using the product of Preparation 21 (0.75g, 2.36 mmol) and 5% palladium on carbon (0.80 g, catalytic, 25 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.32 g, 2.36 mmol), the product of Preparation 30 (0.90 g, 2.36 mmol),and DCC (0.54 g, 2.60 mmol) to yield the desired product (0.86 g, 56%yield) as a light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₃₇H₅₀N₆O₆; 62.75; C, 7.12; H, 12.91; N,found 62.65; C, 6.95; H, 12.76; N, ISMS (M+)—651.

Prepared as in Preparation 38 using the product of Preparation 21 (0.80g, 2.52 mmol) and 5% palladium on carbon (0.80 g, catalytic, 25 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.34 g, 2.52 mmol), the product of Preparation 37 (0.99 g, 2.52 mmol),and DCC (0.57 g, 2.77 mmol) to yield the desired product (0.77 g, 46%yield) as a light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₃₇H₅₀N₆O₆; 63.72; C, 6.87; H, 14.86; N,found 63.45; C, 6.86; H, 14.76; N, ISMS (M+)—660.

Prepared as in Preparation 38 using the product of Preparation 23 (0.80g, 2.05 mmol) and 5% palladium on carbon (0.80 g, catalytic, 25 mL THF)to yield the crude amine. The filtrate was reacted with HOBT (0.28 g,2.05 mmol), the product of Preparation 30 (0.78 g, 2.05 mmol), and DCC(0.46 g, 2.05 mmol) to yield the desired product (0.76 g, 51% yield) asa light yellow foam: ¹H NMR (300 MHz, CDCl₁ ₃)—consistent withstructure; Anal. calcd. for C₄₁H₅₀N₆O₆; 68.12; C, 6.97; H, 11.63; N.found 66.93; C, 6.74; H, 11.24; N. ISMS (M+)—723.

Prepared as in Preparation 38 using the product of Preparation 23 (0.60g, 1.54 mmol) and 5% palladium on carbon (0.60 g, catalytic, 25 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.21 g, 1.54 mmol), the product of Preparation 36 (0.58 g, 1.54 mmol),and DCC (0.35 g, 1.69 mmol) to yield the desired product (0.56 g, 50%yield) as a light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₄₂H₅₂N₆O₅; 69.98; C, 7.27; H, 11.66; N.found 68.71; C, 6.92; H, 11.39; N. ISMS (M+)—721.

Prepared as in Preparation 38 using the product of Preparation 23 (0.20g, 0.51 mmol) and 5% palladium on carbon (0.20 g, catalytic, 25 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.07 g, 0.51 mmol), the product of Preparation 37 (0.20 g, 0.51 mmol),and DCC (0.12 g, 0.51 mmol) to yield the desired product (0.17 g, 45%yield) as a light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₄₂H₄₉N₇O₆; 68.93; C, 6.75; H, 13.40; N.found 67.02; C, 6.54; H, 12.71; N. ISMS (M+)—732.

Prepared as in Preparation 38 using the product of Preparation 24 (0.30g, 0.82 mmol) and 5% palladium on carbon (0.30 g, catalytic, 25 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.11 g, 0.82 mmol), the product of Preparation 36 (0.31 g, 0.82 mmol),and DCC (0.19 g, 0.90 mmol) to yield the desired product (0.32 g, 56%yield) as a light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₄₀H₅₀N₆O₅; 69.14; C, 7.25; H, 12.09; N.found 67.82; C, 7.07; H, 11.62; N. ISMS (M+)—695.

Prepared as in Preparation 38 using the product of Preparation 25 (0.35g, 0.84 mmol) and 5% palladium on carbon (0.35 g, catalytic, 25 mL THF)to give the crude amine. The resulting filtrate was reacted with HOBT(0.11 g, 0.84 mmol), the product of Preparation 36 (0.32 g, 0.84 mmol),and DCC (0.17 g, 0.92 mmol) to yield the desired product (0.22 g, 35%yield) as a light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₄₄H₅₆N₆O₅; 70.56; C, 7.54; H, 11.22; N.found 70.22; C, 7.58; H, 11.21; N. ISMS (M+)—749.

Prepared as in Preparation 38 using the product of Preparation 26 (0.42g, 1.15 mmol) and 5% palladium on carbon (0.40 g, catalytic, 25 mL THF)to yield the crude amine. The filtrate was reacted with HOBT (0.16 g,1.15 mmol), the product of Preparation 30 (0.44 g, 1.15 mmol), and DCC(0.26 g, 1.28 mmol) to yield the desired product (0.41 g, 51% yield) asa light yellow foam: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₉H₄₈N₆O₆; 67.22; C, 6.94; H, 12.06; N. found 67.66;C, 6.95; H, 11.66; N. ISMS (M+)—697.

Example 1

A solution of the product of Preparation 38 (0.52 g, 0.80 mmol) indichloromethane (20 mL) was stirred under nitrogen with anisole (0.4 mL)and triflouroacetic acid (4.0 mL) at ambient temperature for 3 hours.The mixture was concentrated in vacuo to approximately 5 mL and excessdiethyl ether added. The mixture was filtered and rinsed with diethylether to yield the desired product (0.40 g, 65% yield) as an off whitesolid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure; Anal. calcd.for C₃₄H₄₀N₆O₈F₆; 52.71; C, 5.20; H, 10.85; N. found 52.60; C, 5.08; H,10.69; N. FDMS (M+)—546.

Example 2

Prepared as in Example 1 using the product of Preparation 39 (0.86 g,1.22 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.86 g, 85%) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₆H₄₂N₆O₁₀F₆; 51.92; C, 5.08; H, 10.09; N. found51.63; C, 4.96; H, 10.22; N. FDMS (M+)—604.

Example 3

Prepared as in Example 1 using the product of Preparation 40 (0.95 g,1.41 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.82 g, 92%) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₆H₄₄N₆O₈F₆; 53.86; C, 5.53; H, 10.47; N. found 52.73;C, 5.50; H, 10.07; N. FDMS (M+)—574.

Example 4

A solution of the product of Preparation 41 (0.69 g, 1.02 mmol) indichloromethane (10 mL) was stirred under nitrogen with anisole (0.2 mL)and triflouroacetic acid (4.0 mL) at ambient temperature for 3 hours.The mixture was quenched with saturated sodium bicarbonate and stirred10 min. at ambient temperature. Dichloromethane was added and themixture washed with bicarbonante and brine. The organic layer was driedover sodium sulfate, concentrated in vacuo, and redissolved in 2 mLethyl acetate. Diethyl ether (saturated HCl (g), 5 mL) was added and themixture stirred 10 min. The mixture was filtered to yield the desiredproduct (0.57 g, 86% yield) as a white solid: ¹H NMR (300 MHz,CDCl₃)—consistent with structure; Anal. calcd. for C₃₂H₄₂N₆O₄Cl₂; 59.35;C, 6.85; H, 12.98; N. found 58.74; C, 6.77; H, 12.85; N. ISMS (M+)—575.

Example 5

Prepared as in Example 4 using the product of Preparation 42 (0.26 g,0.37 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.19 g, 76%) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₄H₄₈N₆O₄Cl₂; 60.44; C, 7.16; H, 12.44; N. found60.08; C, 7.03; H, 12.06; N. ISMS (M+)—603.

Example 6

Prepared as in Example 4 using the product of Preparation 44 (0.19 g,0.29 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.16 g, 84%) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;

Anal. calcd. for C₃₀H₄₂N₆O₄Cl₂; 57.97; C, 6.81; H, 13.52; N. found57.54; C, 6.36; H, 13.04; N. FDMS (M+)—549.

Example 7

Prepared as in Example 4 using the product of Preparation 45 (0.84 g,1.29 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.69 g, 86%) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;

Anal. calcd. for C₂₉H₃₈N₆O₅C₂; 55.86; C, 6.47; H, 13.48; N. found 55.31;C, 6.52; H, 13.01; N. ISMS (M+)—551.

Example 8

Prepared as in Example 4 using the product of Preparation 46 (0.75 g,1.13 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.62 g, 87%) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₀H₃₇N₇O₄Cl₂; 56.96; C, 6.21; H, 15.50; N. found55.48; C, 6.03; H, 14.63; N. ISMS (M+)—560.

Example 9

Prepared as in Example 4 using the product of Preparation 43 (0.82 g,1.16 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.71 g, 90%) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₃H₄₆N₆O₅Cl₂; 58.49; C, 6.84; H, 12.40; N. found55.40; C, 6.48; H, 11.80; N. ISMS (M+)—605.

Example 10

Prepared as in Example 4 using the product of Preparation 47 (0.76 g,1.05 mmol), triflouroacetic acid (2.0 mL), anisole (0.2 mL), anddichloromethane (8.0 mL) to yield the desired product (0.76 g, 85%yield) as an off white solid: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₄₀H₄₄N₆O₈F₆; 56.47; C, 5.21; H, 9.88; N.found 56.24; C, 5.32; H, 9.86; N. ISMS (M+)—623.

Example 11

Prepared as in Example 4 using the product of Preparation 48 (0.52 g,0.72 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.47 g, 94%) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₇H₄₆N₆O₃Cl₂; 64.06; C, 6.68; H, 12.11; N. found62.18; C, 6.59; H, 11.78; N. ISMS (M+)—621.

Example 12

Prepared as in Example 4 using the product of Preparation 50 (0.32 g,mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.26 g, %) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₅H₄₄N₆O₃Cl₂; 62.96; C, 6.64; H, 12.59; N. found60.05; C, 6.31; H, 11.98; N. FDMS (M+)—595.

Example 13

Prepared as in Example 4 using the product of Preparation 51 (0.22 g,0.29 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.19 g, %) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₉H₅₀N₆O₃Cl₂; 64.90; C, 6.98; H, 11.64; N. found66.48; C, 7.24; H, 11.96; N. FDMS (M+)—649.

Example 14

Prepared as in Example 4 using the product of Preparation 49 (0.96 g,1.31 mmol), triflouroacetic acid (4.0 mL), anisole (0.4 mL), anddichloromethane (20 mL) to yield the desired product (0.54 g, 59%) as apale yellow solid: ¹H NMR (300 MHz, CDCl₃)—consistent with structure;Anal. calcd. for C₃₇H₄₃N₇O₃Cl₂; 63.06; C, 6.15; H, 13.91; N. found58.22; C, 5.48; H, 12.32; N. ISMS (M+)—632.

Example 15

Prepared as in Example 1 using the product of Preparation 52 (0.41 g, 0.59 mmol), triflouroacetic acid (2.0 mL), anisole (0.2 mL), anddichloromethane (8.0 mL) to yield the desired product (0.48 g, 99%yield) as an off white solid: ¹H NMR (300 MHz, CDCl₃)—consistent withstructure; Anal. calcd. for C₃₈H₄₂N₆O₈F₆; 55.34; C, 5.13; H, 10.19; N.found 55.60; C, 4.92; H, 9.89; N. ISMS (M+)—597.

EXAMPLES PART 4

To a solution of Preparation 306 from Examples Part 2 (1.58 g, 10mmol)and (1R,2S)-(+)-cis-1-amino-2-indanol (1.49 g, 10 mmol) in methanol(10 mL) was added sodium bicarbonate (840 mg, 10 mmol) and water (5 mL).The resulting mixture was stirred at room temperature overnight. Thesolvent was removed in vacuo and the residue partitioned between ethylacetate and brine. The organic phase was dried (MgSO₄) and concentratedin vacuo. The residue was purified by flash chromatography on silicaeluting with 80% ethyl acetate/hexanes then 100% ethyl acetate, to give1.65 g, 67% of the desired product as a tan foam. ¹H NMR (CDCl₃) δ7.70(s, 1H), 7.5-7.3 (m, 4H), 7.2 (d, J=9 Hz, 1H), 5.65 (d, J=5 Hz, 1H),4.97 (m, 1H), 3.83 (br s, 1H), 3.35 (dd, J=6.5, 16 Hz, 1H), 3.12 (dd,J=4, 16 Hz, 1H).

To a solution of Preparation 1 (490 mg, 2 mmol) in dry DMF (6 mL) wasadded t-butyldimethylsilyl chloride (300 mg, 2 mmol) and imidazole (136mg, 2 mmol). The solution was stirred at room temperature for 24 h andan additional 50 mg of t-butyldimethylsilyl chloride was added. Afterstirring an additional 16 h the solvent was removed in vacuo. Flashchromatography of the residue, eluting with 50% ethyl acetate/hexanesgave 540 mg, 75% of the desired product as a white solid. ¹H-NMR isconsistent with the desired product. MS (ion spray) 360 (M+1). Anal.Calcd for C₁₈H₂₅N₃O₃Si, C, 60.14; H, 7.01; N, 11.69; Found: C, 60.40; H,6.91; N, 11.58; [a]_(D)+51.6 (c=10).

10% Pd on carbon (350 mg) was wet under nitrogen atmosphere with dry THF(5 mL). A solution of Preparation 2 (500 mg, 1.39 mmol) in dry THF (15mL) was added and the mixture hydrogenated for 2 h under 40 psi hydrogengas pressure. The catalyst was removed by filtration through celite andthe filtrate concentrated in vacuo to approximately a volume of 10 mL.To this solution was added Preparation 4 of Examples Part 1 (532 mg, 1.4mmol), HOBt hydrate (214 mg, 1.4 mmol), DCC (289 mg, 1.4 mmol), and themixture stirred at room temperature overnight. The precipitated DCU wasremoved by filtration. The filtrate was diluted with ethyl acetate andthe organic solution washed with 1N hydrochloric acid solution,saturated aqueous sodium bicarbonate solution, and brine then dried(MgSO₄) and concentrated in vacuo. Flash chromatography of the residue,eluting with 80% ethyl acetate/hexanes gave 570 mg, 59% of the desiredproduct as a white foam. ¹H-NMR is consistent with the desired product.MS (ion spray) 692 (M+1). IR 1709, 1669 cm⁻¹.

Example 1

A compound of Preparation 3 (440 mg, 0.63 mmol) was dissolved in glacialacetic acid that had been previously saturated with dry hydrogenchloride gas (10 mL, approx. 3N in HCl). The mixture was stirred at roomtemperature for 30 min, then water (0.5 mL) was added and the mixturestirred an additional 1 h. The mixture was concentrated in vacuo,toluene was added and the solvent removed in vacuo to give a tan solid.This material was converted to the free base by partitioning betweenchloroform and saturated aqueous sodium bicarbonate solution. Theorganic phase was dried (MgSO₄) and concentrated in vacuo. Flashchromatography of the residue, eluting with 5% methanol/chloroformcontaining a trace of ammonium hydroxide gave two products, The morepolar product, 80 mg, 23% yield was the desired compound. MS 478 (M+).The more polar product was reconverted to the bis hydrochloride salt bydissolving in chloroform and adding ethyl ether that had been previouslysaturated with dry hydrogen chloride gas. ¹H NMR (DMSO-d₆) δ11.25 (br s,1H), 8.6 (d, J=7 Hz, 1H), 8.4-8.1 (m, 5H), 7.4≧7.15 (m, 10H), 7.02 (s,1H), 5.75 (d, J=5 Hz, 1H), 4.70 (m, 1H), 4.56 (m, 1H), 4.45 (m, 2H),3.65 (m, 2H), 3.12 (dd, J=6.5, 16 Hz, 1H)), 2.82 (dd, J=4, 16 Hz, 1H),1.45 (s, 6H). The less polar product was identical to acetyl analog (theproduct from Example 172, Examples Part 2A) (160 mg, 48% yield).

To a 0° C. solution of Preparation 1 (490 mg, 2 mmol) in pyridine (10mL) was added acetic anhydride (0.2 mL, 2 mmol). The mixture was allowedto warm to room temperature while stirring overnight. The solvent wasremoved in vacuo and the residue dissolved in ethyl acetate. The organicsolution was washed with 1N hydrochloric acid solution, saturatedaqueous sodium bicarbonate solution, and brine then dried (MgSO₄) andconcentrated in vacuo. Flash chromatography of the residue on silicagel, eluting with 50% ethyl acetate/hexanes gave 420 mg, 73% of thedesired product as a colorless oil. ¹H-NMR is consistent with thedesired product. MS (ion spray) 288 (M+1). Anal. Calcd for C₁₄H₁₃N₃O₄,C, 58.53; H, 4.56; N, 14.63. Found: C, 58.30; H, 4.62; N, 14.41;

Racemic trans-1-amino-2-hydroxyindan was prepared from racemic indeneoxide according to the method of D. R. Boyd, N. D. Sharma, N. I. Bowers,P. A. Goodrich, M. R. Groocock, A. J. Blacker, D. A. Clarke, T. Howard,H. Dalton. Tetrahedron Asymmetry 7, 1559-1562, 1996.

To a solution of Preparation 306 from Examples Part 2 (1.85 g, 11.67mmol)and trans-1-amino-2-hydroxyindan (1.74 g, 11.76 mmol) in methanol(15 mL) was added sodium bicarbonate (1.0 g, 11.9 mmol) and water (8mL). The resulting mixture was stirred at room temperature overnight.The solvent was removed in vacuo and the residue partitioned betweenethyl acetate and brine. The organic phase was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with 80% ethyl acetate/hexanes to give 1.73 g, 60%of the desired product as a tan foam. ¹H-NMR is consistent with thedesired product. MS (ion spray) 246 (M+1). Anal. Calcd for C₁₂H₁₁N₃O₃,C, 58.77; H, 4.52; N, 17.13; Found: C, 58.87; H, 4.65; N, 17.18.

To a solution of Preparation 5 (290 mg, 1.18 mmol) in pyridine (10 mL)was added acetic anhydride (0.2 mL, 2 mmol). The mixture stirred at roomtemperature overnight. The solvent was removed in vacuo and the residuedissolved in ethyl acetate. The organic solution was washed with 1Nhydrochloric acid solution, saturated aqueous sodium bicarbonatesolution, and brine then dried (MgSO₄) and concentrated in vacuo to give280 mg, 82% yield of the desired product as an off-white foam. ¹H-NMR isconsistent with the desired product. MS (ion spray) 288 (M+1). IR 1744,1549 cm⁻¹

10% Pd on carbon (260 mg) was wet under a nitrogen atmosphere with dryTHF (5 mL). A solution of Preparation 6 (275 mg, 0.95 mmol) in dry THF(7 mL) was added and the mixture hydrogenated for 1.5 h under 40 psihydrogen gas pressure. The catalyst was removed by filtration throughcelite and the filtrate concentrated in vacuo to approximately a volumeof 8 mL. To this solution was added Preparation 4 of Examples Part 1(380mg, 1.0 mmol), HOBt hydrate (153 mg, 1.0 mmol), DCC (206 mg, 1.0 mmol),and the mixture stirred at room temperature for 60 h. The precipitatedDCU was removed by filtration. The filtrate was diluted with ethylacetate and the organic solution washed with 1N hydrochloric acidsolution, saturated aqueous sodium bicarbonate solution, and brine thendried (MgSO₄) and concentrated in vacuo. Radial chromatography of theresidue, eluting with 80% ethyl acetate/hexanes gave 310 mg, 52% of thedesired product. ¹H-NMR is consistent with the desired product. MS (ionpray) 620 (M+1). Anal. Calcd for C₃₃H₄₁N₅O₇, C, 3.96; H, 6.67; N, 11.30;Found: C, 63.30; H, 6.86; N, 11.13;

Example 2

A compound of Preparation 7 (290 mg, 0.46 mmol) was dissolved in glacialacetic acid that had been previously saturated with dry hydrogenchloride gas (10 mL, approx. 3N in HCl). The mixture was stirred at roomtemperature for 20 min then concentrated in vacuo, toluene was added andthe solvent removed in vacuo to give a yellow solid. This material wasconverted to the free base by partitioning between ethyl acetate and 0.1N aqueous sodium hydroxide solution. The organic phase was dried (MgSO₄)and concentrated in vacuo. Flash chromatography of the residue, elutingwith 5% methanol/chloroform gave the desired product. The hydrochloridesalt was reformed by dissolving the product in glacial acetic acid thathad been previously saturated with dry hydrogen chloride gas (5 mL,approx. 3N in HCl), then toluene was added and the solvent removed invacuo to give 140 mg, 50% yield of the desired product a white solid. ¹HNMR (DMSO-d₆) δ11.05 (br s, 1H), 8.55 (d, J=8 Hz, 1H), 8.24 (br s, 2H),8.10 (br s, 1H), 7.22-7.05 (m, 10H), 5.95 (d, J=7 Hz, 1H), 5.50 (m, 1H),5.30 (br s, 2H), 4.78 (m, 1H), 4.52, (s, 2H), 3.73 (m, 2H), 3.52 (dm,J=16 Hz, 1H), 2.98 (dd, J=7, 16 Hz, 1H), 2.04 (s, 3H), 1.50 9s, 6H). MS(ion spray) 520 (M+1). Anal. Calcd for C₂₈H₃₅Cl₂N₅O₅+0.4 H₂O. C, 56.02;H, 5.96; N, 11.67; Found: C, 56.33; H, 6.33; N, 11.27.

Preparation 391 of Examples Part 2A (950 mg, 4.35 mmol) was dissolved inTHF (20 mL) and methyl isocyanate (0.3 mL, 5 mmol) was added. After 4 hof stirring there was no apparent change by TLC. An additional 10 mmolof methyl isocyanate was added along with triethyl amine (0.7 mL, 5mmol) and the mixture was stirred an additional 60 h. The whiteprecipitate that formed was collected by filtration and dried in vacuoto give 1.04 g, 87% of the desired urea. ¹H-NMR is consistent with thedesired product. MS (ion spray) 276 (M+1). Anal. Calcd for C₁₂H₁₃N₅O₃,C, 52.36; H, 4.76; N, 25.44; Found: C, 52.61; H, 4.74; N, 25.25.

10% Pd on carbon (550 mg) was wet under a nitrogen atmosphere with ethylacetate (5 mL). A slurry of Preparation 8 (550 mg, 2.0 mmol) in ethylacetate (40 mL), methanol (40 mL) and acetic acid (1 mL) was added andthe mixture hydrogenated for 2 h under 40 psi hydrogen gas pressure. Thecatalyst was removed by filtration through celite and the filtrateconcentrated in vacuo. Toluene was added and the mixture reconcentratedin vacuo to give a purple solid. This solid was dissolved in THF (20 mL)and to this solution was added

Preparation 4 of Examples Part 1 (760 mg, 2.0 mmol), HOBt hydrate (306mg, 2.0 mmol), DCC (412 mg, 2.0 mmol), and triethyl amine (0.28 mL, 2.0mmol). The mixture stirred at room temperature overnight. Theprecipitated DCU was removed by filtration. The filtrate was dilutedwith ethyl acetate and the organic solution washed with 1N hydrochloricacid solution, saturated aqueous sodium bicarbonate solution, and brinethen dried (MgSO₄) and concentrated in vacuo. Flash chromatography ofthe residue, eluting with a step gradient of 2% methanol/ethyl acetate,to 5% methanol/ethyl acetate, to 5% methanol/1% acetic acid/ethylacetate, to 10% methanol/1% acetic acid/ethyl acetate gave 240 mg, 19%of the desired product as an off-white solid. ¹H-NMR is consistent withthe desired product. MS (ion spray) 608 (M+1).

Example 4

A compound of Preparation 9 (210 mg, 0.34 mmol) was dissolved in glacialacetic acid that had been previously saturated with dry hydrogenchloride gas (5 mL, approx. 3N in HCl). The mixture was stirred at roomtemperature for 1 h then concentrated in vacuo, toluene was added andthe solvent removed in vacuo to give a gum. The residue was dissolved inmethanol (2 mL), toluene was added and the solvents removed in vacuo togive 190 mg of the desired product as white powder. ¹H NMR (DMSO-d₆) d11.20 (br s, 1H), 8.71 (br s, 1H), 8.62 (d, J=7.5 Hz, 1H), 8.25 (br s,2H), 7.72 (d, J=8.5 Hz, 1H), 7.34-7.12 (m, 9H), 7.04 (t, J=7.5 Hz, 1H),6.86 (br s, 1H), 5.42 (ABq, J=14 Hz, 2H), 4.73 (q, J=7 Hz, 1H), 4.53 (s,2H), 3.73 (m, 2H) 2.65 (s, 3H), 1.50 (s, 6H). MS (ion spray) 508 (M+1).

3-Aminobenzyl alcohol(615 mg, 5 mmol) was dissolved in methylenechloride (10 mL) and methyl isocyanate (0.3 mL, 5 mmol) was added. Themixture was stirred at room temperature overnight. The white precipitatethat formed was collected by filtration and dried in vacuo to give 775mg, 86% of the desired urea. ¹H-NMR is consistent with the desiredproduct. MS (ion spray) 181 (M+1) . Anal. Calcd for C₉H₁₂N₂O₂, C, 59.99;H, 6.71; N, 15.55; Found: C, 60.23; H, 6.68; N, 15.37.

To a 0° C. solution of Preparation 10 (540 mg, 3 mmol) in THF (30 mL)was added triethyl amine (0.46 mL, 3.3 mmol) and methanesulfonylchloride (0.255 mL, 3.3 mmol). The mixture was stirred at 0° C. for 1 hat which time TLC (EtOAc) indicated the alcohol had been consumed and aless polar product had formed. The solvent was removed in vacuo and theresidue dissolved in dry DMF (10 mL). Potassium carbonate (966 mg, 7mmol) and 4-nitro imidazole (339 mg, 3 mmol) were added, and the mixturewas stirred at room temperature overnight. The DMF was removed in vacuo,the residue dissolved in chloroform/isopropanol (3/1), and washed withwater, brine, then dried (MgSO₄) and concentrated to a solid. Flashchromatography on silica gel eluting with 3% methanol in ethyl acetategave the desired product 410 mg 50%, contaminated with approximately 20%of the undesired 4-alkylated isomer (by NMR analysis). Anal. Calcd forC₁₂H₁₃N₅O₃, C, 52.36; H, 4.76; N, 25.44. Found: C, 52.66; H, 4.64; N,25.31.

10% Pd on carbon (380 mg) was wet under a nitrogen atmosphere with ethylacetate (20 mL). A solution of Preparation 11 (380 mg, 1.4 mmol) inmethanol (20 mL) was added and the mixture hydrogenated for 2 h under 40psi hydrogen gas pressure. The catalyst was removed by filtrationthrough celite and the filtrate concentrated in vacuo. THF was added andthe mixture reconcentrated in vacuo to give a solid. This solid wasdissolved in THF (10 inL) and to this solution was added Preparation 4from Examples Part 1(532 mg, 1.4 mmol), HOBt hydrate (214 mg, 1.4 mmol),DCC (289 mg, 1.4 mmol) . The mixture stirred at room temperatureovernight. The precipitated DCU was removed by filtration. The filtratewas diluted with ethyl acetate and the organic solution washed withsaturated aqueous sodium bicarbonate solution, and brine then dried(MgSO₄) and concentrated in vacuo. Flash chromatography of the residue,eluting with a step gradient of 2% methanol/ethyl acetate, to 10%methanol/ethyl acetate gave 400 mg, of impure product as an off-whitesolid. Radial chromatography, 5% methanol/chloroform gave the desiredproduct, 370 mg, 44% as a yellowish tinted foam. ¹H-NMR is consistentwith the desired product. MS (ion spray) 608 (M+1). Anal. Calcd forC₃₁H₄₁N₇O₆+0.2CHCl₃ C, 59.33; H, 6.58; N, 15.52. Found: C, 59.21; H,6.65; N, 15.18.

Example 5

To a compound of Preparation 12 (0.3 g, 0.5 mmol) stirring indichloromethane (6 mL) at room temperature was added trifluoroaceticacid (2 mL). After 2 h, the reaction mixture was concentrated todryness. The residue was partitioned between ethyl acetate and saturatedsodium bicarbonate and was then extracted with ethyl acetate. Thecombined organics were washed with brine, dried over sodium sulfate andconcentrated to dryness. The residue was chromatographed over silica gelusing ethanol/chloroform as eluant to yield 0.12 g (49%) of the desiredproduct as a white foam. ¹H-NMR is consistent with structure; MS (ionspray) 508.3 (M+1); Anal. Calc'd for C₂₆H₃₃N₇O₄.0.41CHCl₃: C, 57.00; H,6.05; N, 17.62. Found: C, 57.17; H, 6.24; N, 17.22.

EXAMPLES PART 5 Preparation 1 Methyl2R-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-2-phenylacetate

To a solution of N-[(1,2-dimethylethoxy)carbonyl]-2-methylalanine (5.04g, 24.79 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (4.43 g, 24.79mmol) in 100 mL of THF was added N-methylmorpholine (5.45 mL, 49.58mmol). After 1 h, (R)-phenylglycine methyl ester hydrochloride (5.0 g,24.79 mmol) was added in one portion, and the reaction mixture wasstirred at room temperature for 16 h. The reaction was concentrated invacuo, and the resulting residue was dissolved in 100 mL each of EtOAcand 10% (w/w) aqueous citric acid. The phases were separated and theorganic layer was washed with saturated aqueous NaHCO₃ and saturatedaqueous NaCl, dried over Na₂SO₄, filtered and concentrated in vacuo togive 8.51 g (98 %) of a white solid. ¹H NMR (DMSO, 300 MHz) d 8.05 (m,1H), 7.40 (m, 5H), 6.90 (br s, 1H), 5.40 (d, 1H) , 3.65 (s, 3H), 1.30(m, 15H); ¹³C NMR (DMSO, 75 MHz) 174.2, 170.9, 154.3, 136.8, 128.4,128.1, 128.0, 127.4, 78.2, 56.0, 52.3, 28.0, 25.2, 24.7 ppm; Anal.Calcd. for C₁₈H₂₆N₂O₅: C, 61.70; H, 7.48; N, 7.99. Found: C, 61.50; H,7.36; N, 8.19.

Preparation 2(R)-2-[(Tert-butoxy)carbonylamino]-2-methyl-N-({N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}phenylmethyl)propanamide

To a 0° C. solution of the methyl ester in Example 1, (1.0 g, 2.85 mmol)in dioxane (19 mL) and H₂O (9.5 mL) was added LiOH (0.682 g, 28.5 mmol).The reaction stirred for 40 min and was diluted with 50 mL of EtOAc. ThepH was adjusted to 3 with conc. HCl and the phases were separated. Theaqueous layer was extracted with EtOAc (2×25 mL). The combined organicswere dried over Na₂SO₄, filtered and concentrated in vacuo to give 958mg of the acid which was used as is in subsequent reactions.

N-methylmorpholine (0.25 mL, 2.27 mmol) was added to a suspension of2-chloro-4,6-dimethoxy-1,3,5-triazine (405 mg, 2.27 mmol) and2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-2-phenylacetic acid (570 mg, 1.69in mol) in CH₂Cl₂ (7 mL) and THF (2 mL) at 23° C. The mixture stirredfor 2 h and 2-(4-amino imidazolyl)-2-phenyl-1-pyrrolidinylethan-1-onedihydrochloride (779 mg, 2.27 mmol) was added in one portion. After 16h, the reaction was diluted with EtOAc (50 mL) and 10% (w/w) aqueouscitric acid. The phases 25 were separated, and the organic layer waswashed with 20 mL each of saturated aqueous NaHCO₃ and saturated aqueousNaCl, dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by flash chromatography (gradient 2/98 to 6/94 MeOH/CH₂Cl₂)to give 405 mg (40 %) of the title compound. ¹H NMR (CDCl₃, 300 MHz) d10.61 (m, 1H), 7.75 (s, 1H), 7.45-7.15 (m, 12H), 5.95 (s, 1H), 5.80 (m,1H), 3.60-3.38 (m, 3H), 3.10 (m, 1H), 2.15 (m, 1H), 1.98-1.65 (m, 3H),1.50-1.05 (m, 15H); IR (CHCl₃) 3400, 3000,1706, 1661, 1486, 1455, 1157cm⁻¹; MS (electrospray) m/z 588 (M+H), 589 (M−H), 587.

Example 1(R)-2-Amino-2-methyl-N-({N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}phenylmethyl)propanamide,bis-trifluoroacetate

Trifluoroacetic acid (1.4 mL, 18.3 mmol) was added to a solution of acompound of Example 2 (360 mg, 0.611 mmol), anisole (0.20 mL, 1.83 mmol)and CH₂Cl₂ (14 mL). After 4 h the solution was concentrated to an oilwhich was dissolved in CH₂Cl₂ (3.0 mL). This solution was added dropwiseto Et₂O (25 mL) with vigorous stirring, and a white precipitate formed.After 12 h, the solid was filtered and washed with Et₂O (20 mL). The wetcake was dried at 40° C. in a vacuum oven for 12 h to yield 391 mg(91%). ¹H NMR (DMSO-d₆, 300 MHz) d 10.70 (d, J =2.5 Hz, 1H), 8.66 (d,J=6.7 Hz, 1H), 8.02 (m, 3H), 7.54-7.10 (m, 12H), 6.39 (s, 1H), 5.58 (m,1H), 3.60 (m, 1H), 3.30 (m, 2H), 2.90 (m, 1H), 1.80-1.55 (m, 4H),1.07-0.70 (m, 6H); IR (KBr) 3064, 3035, 2980, 1672, 1575, 1539, 1497,1201, 1133, 721, 700 cm⁻¹; MS (electrospray) m/z (freebase) 488;(freebase M+H), 489 (freebase M−H), 487.

Preparation 3(R)-2-[(Tert-butoxy)carbonylamino]-2-methyl-N-[(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)phenylmethyl]propanamide

N-methylmorpholine (0.16 mL, 1.49 mmol) was added to a suspension of2-chloro-4,6-dimethoxy-1,3,5-triazine (268 mg, 1.53 mmol),2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-2-phenylaceticacid (502 mg, 1.49 mmol), CH₂Cl₂ (7 mL) and THF (2 mL) at 23° C. Theheterogeneous reaction stirred for two hours and2-(4-aminoimidazolyl)-1-(4-methylpiperidyl)-2-phenylethan-1-onedihydrochloride (613 mg, 1.65 mmol) was added. The mixture was stirredfor 15.5 h, and EtOAc (40 mL) and 10% (w/w) aqueous citric acid (18 mL)were added. The layers were separated, and the organic layer wasextracted with 15 mL each of saturated NaHCO₃ and saturated NaCl. Theorganic layer was dried (MgSO₄), concentrated in vacuo to 590 mg ofsolid, and purified by flash chromatography (10% i-PA/CHCl₃) to yield440 mg (48%) of a foamy solid: ¹H NMR (CDCl₃, 300 MHz) d 10.34 (m, 1H),7.67 (s, 1H), 7.40-7.19 (m, 12H), 6.10 (m, 1H), 5.73 (m, 1H), 4.57 (m,1H), 3.84 (m, 1H), 3.60 (m, 1H), 2.95 (m, 1H), 2.74-2.58 (m, 1H),1.65-0.79 (m, 23H); ¹³C NMR (CDCl₃, 75 MHz) 174.0, 167.0, 165.3, 137.7,136.7, 134.2, 133.5, 133.4, 129.4, 129.3, 129.2, 129.2, 128.7, 128.5,128.5, 128.3, 128.2, 128.0, 127.2, 127.2, 108.1, 62.1, 62.0, 62.0, 61.9,57.1, 56.6, 46.0, 46.0, 45.8, 429, 34.2, 33.6, 33.5, 30.8, 30.7, 28.2,21.5, 21.4 ppm; IR (CDCl₃) 1456, 1487, 1560, 1661, 1707, 3010 cm⁻¹; MS(electrospray) m/z 617 (M+H), 438 & 615 (M−H), 436.

Example 2(R)-2-Amino-2-methyl-N-[(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)phenylmethyl]propanamide bis-trifluoroacetate

Trifluoroacetic acid (1.5 mL, 19.9 mmol) was added to a solution of acompound of Example 4 (410 mg, 0.66 mmol), anisole (0.22 mL, 2.0 mmol)and CH₂Cl₂ (16 mL). After 5 h the solution was concentrated to an oilwhich was dissolved in CH₂Cl₂ (3.5 mL). This solution was added dropwiseto Et₂O (30 mL) with vigorous stirring, and a white precipitate formed.After 30 min the solid was filtered and washed with copious Et₂O. Thewet cake was dried in a room temperature vacuum desiccator overnight toyield 283 mg (58%) of a white, hygroscopic powder: mp 182° C. (dec); ¹HNMR (DMSO-d₆, 300 MHz) d 10.79 (d, J=2.7 Hz, 1H), 8.72 (d, J=6.5 Hz,1H), 8.15 (m, 2H), 7.54-7.20 (m, 11H), 7.19 (m, 1H), 6.73 (d, J=14.2 Hz,1H), 5.61 (d, J=6.7 Hz, 1H) 4.36 (m, 1H), 3.72 (m, 1H), 2.69-2.48 (m,2H), 1.59-1.24 (m, 9H), 1.07-0.70 (m, 5H); ¹³C NMR (DMSO-d₆, 75 MHz)171.5, 171.4, 166.4, 165.6, 165.6, 165.4, 165.4, 158.3, 157.9, 137.2,137.1, 137.0, 136.2, 136.1, 135.6, 135.5, 135.4, 133.2, 133.1, 129.2,128.9, 128.7, 128.4 128.3, 128.3, 128.1, 128.0, 127.9, 127.6, 107.2,107.2, 97.8, 60.3, 60.3, 60.0, 57.0, 56.9, 56.6, 45.2, 42.2, 42.0, 42.0,34.0, 33.9, 33.3, 3.2, 33.0, 30.0, 23.2, 23.2, 21.5, 21.4 ppm; IR (KBr)1137, 1201, 1540, 1576, 1670, 2955 cm⁻¹; MS (electrospray) 517 (freebaseM+H), 438 & 515 (freebase M−H).

EXAMPLES PART 6 Example 1 Chromatographic Separation

Diastereomeric secretagogue compounds are separated on a 8×15 cmProchrom® column packed with a Kromasilo® CHI-DMB chiral phase. Thechromatographic eluent consisted of 12% to 15% 3A alcohol, 0.2%dimethylethylamine in heptane. One to two gram loadings of mixtures ofdiastereomers have been separated by this technique. The active isomerhas been demonstrated to be the second eluting component. Isolation ofthe desired isomer is completed by evaporation of the solvent by using aroto evaporator.

Since this is a chiral phase, enantiomers of the individualdiastereomers are also resolved to yield compounds which areenantiomerically pure.

The procedure for packing the Prochrom® column, separation of thediastereomeric secretagogue SAR candidates, and analysis of the purifiedcompounds is provided as follows:

Materials

Chemicals:

Kromasil® CHI-I, 10 m CSP Bulk

3A alcohol, QA 041N

Heptane, QD440N

Dimethylethylamine, Aldrich

Equipment:

8 cm Prochrom® column

Prochrom® LC-80 pumping system, fraction collector

Chromatography

Column Preparation: Slurry 500 grams of Kromasil® CHI bulk packing in400 ml of propanol. Pack in 8×16 cm Prochrom® column. Equilibrate witheluent consisting 13% 3A alcohol, 0.2% dimethylethylamine in heptane ata flow rate of 250 ml/min. Detector setting is 260 nm to 270 nm for the200 mg loading per run. Change wavelength to 280 nm for 1.0 gramloadings.

Sample preparation: Dissolve approximately 1.0 grams of secretagoguemixture in small amount of 3A alcohol and dilute with approximately 50ml of eluent.

Chromatographic separation: The first isomer from each series elutes inrange of 6 to 8 minutes. The second isomer elutes in range of 8 to 10minutes. Shave the front and back of isomer 1 to eliminate otherisomeric impurities.

Fraction work up: Strip fractions to dryness using roto vap.

Sample Analysis Conditions:

a. Operating Conditions

Column: 0.46×25 cm Kromasil® CHI

Eluent: 15% ethanol, 0.2% dimethylethylamine in heptane

Flow Rate: 1.0 ml/min

Temperature: ambient

uv: 250 nm

Injection: as needed

b. System Suitability

I) isomer 1 elutes in 5 to 6 minutes, isomer 2 elutes in 8 to 10 minutes

C. Analysis Procedure

I) calculate the diastereomeric excess of each isolated isomer.

Both diastereomerically and optically pure secretagogue compounds areproduced by this process.

Example 2 Chiral Synthesis of Nitroimidazole (L-isomer)

Boc-L-α-Phenylglycine (2.0 g, 9.12 mmol) was dissolved in 15 mLanhydrous THF and cooled to 0° C. DCC (1.97 g, 9.58 mmol) was added,followed by the addition of 4-methylpiperidine (1.08 mL, 9.12 mmol) andHOBt (1.29 g, 9.58 mmol). After stirring 30 min the ice bath was removedand stirring continued overnight at ambient temperature. The reactionwas filtered, concentrated, then diluted with EtOAc and washed with 10%aqueous sodium bicarbonate (1×50 mL), 0.1N HCl (1×50 mL), and dried oversodium sulfate. Filtered, and concentrated to 3.2 g of a crude yellowoil. The oil was purified was radial chromatography eluting with 30:70EtOAc:Hexanes. The appropriate fractions were concentrated to 2.5 g (83%yield) of a colorless foam. ¹H-NMR (d, CDCl₃, 250 MHz, rotamers present)0.60 (d, J=7.5 Hz, 1.5 H), 0.77 (d, J=7.5 Hz, 1.5 H), 1.00-1.50 (m, 5H),1.25 (s, 9H), 2.45 (m, 1H), 2.80 (m, 1H), 3.62 (m, 1H), 4.43 (m, 1H),5.43 (m, 1H), 6.02 (d, J=8 Hz, 1H), 7.10-7.30 (m, 5H); MS (ion spray)333.5 (M+1); [α]_(D)=+95.9 (MeOH); Anal. Calc'd for C₁₉H₂₈N₂O₃: C,68.65;H, 8.49; N, 8.43. Found: C, 69.04; H, 8.51; N, 8.91.

The Boc group was removed from the above compound (1.09 g, 3.28 mmol) bydissolving in 3 mL of methylene chloride and added 3 mL oftrifluoroacetic acid. After stirring 1 h at room temperature thereaction was concentrated in vacuo (3×CH₂Cl₂). The compound was vacuumdried to 1.5 g (100%) of the ditrifluoroacetic acid salt. ¹H-NMR (d,CDCl₃, 400 MHz, equal intensity rotamers present at room temperature)0.01 (m, 0.5H), 0.70 (d, J=7.5 Hz, 1.5 H), 0.83 (m, 0.5H), 0.88 (d,J=7.5 Hz, 1.5 H), 1.00-1.60 (m, 4H), 2.55 (m, 1H), 2.90 (m, 1H), 3.52(m, 1H), 4.35 (m, 1H), 5.42 (m, 1H), 7.32-7.43 (m, 5H), 8.18 (br s, 2H),9.30 (br s, 2H); MS (ion spray) 233.1 (M+1);[α]_(D)=+19.7 (1N HCl).

The above amine (1.5 g, 3.26 mmol) was dissolved in 10 mL methanol and10 mL water and cooled to 0° C. Sodium bicarbonate (0.58 g, 6.85 mmol)was added and stirred 10 min followed by the addition of1,4-dinitroimidazole. The solution quickly turned bright yellow andafter stirring 30 min the ice bath was removed and stirring continuedovernight at ambient temperature. The product was extracted into CH₂Cl₂,dried over sodium sulfate, filtered, and concentrated to 0.93 g of acrude white foam. A pure sample is obtained by crystallization fromEtOAc (0.64 g, 60%). ¹H-NMR (d, CDCl₃, 400 MHz, rotamers present) 0.05(m, 0.5H), 0.59 (d, J=7.5 Hz, 1.5 H), 0.72 (d, J=7.5 Hz, 1.5 H), 0.79(m, 0.5H), 0.93 (m, 0.5H), 1.14 (m, 0.5H), 1.23-1.56 (m, 3H), 2.44 (m,1H), 2.82 (m, 1H), 3.36 (m, 1H), 4.37 (m, 1H), 5.88 (s, 0.5H), 5.90 (s,0.5H), 7.02 (s, 1H), 7.10-7.30 (m, 5H), 7.52 (s, 1H); MS (ion spray)329.3 (M+1); [α]_(D)=+177.6 (MeOH); 98% ee by chiral HPLC; Anal. Calc'dfor C₁₇H₂₀N₄O₃: C, 62.18;H, 6.14; N, 17.06. Found: C, 62.25; H, 6.08; N,17.09.

Example 3 Chiral Synthesis of Nitroimidazole D-isomer

Boc-D-α-Phenylglycine (2.0 g, 9.12 mmol) was dissolved in 15 mLanhydrous THF and cooled to 0° C. DCC (1.97 g, 9.58 mmol) was added,followed by the addition of 4-methylpiperidine (1.08 mL, 9.12 mmol) andHOBt (1.29 g, 9.58 mmol). After stirring 30 min the ice bath was removedand stirring continued overnight at ambient temperature. The reactionwas filtered, concentrated, then diluted with EtOAc and washed with 10%aqueous sodium bicarbonate (1×50 mL), 0.1N HCl (1×50 mL), and dried oversodium sulfate. Filtered, and concentrated to 3.1 g of a crude yellowoil. The oil was purified was radial chromatography eluting with 30:70EtOAc:Hexanes. The appropriate fractions were concentrated to 2.2 g (73%yield) of a colorless foam. ¹H-NMR (d, CDCl₃, 250 MHz, rotamers present)0.60 (d, J=7.5 Hz, 1.5 H), 0.77 (d, J=7.5 Hz, 1.5 H), 1.00-1.50 (m, 5H),1.25 (s, 9H), 2.45 (m, 1H), 2.80 (m, 1H), 3.62 (m, 1H), 4.43 (m, 1H),5.43 (m, 1H), 6.02 (d, J=8 Hz, 1H), 7.10-7.30 (m, 5H); MS (ion spray)333.5 (M+1); [α]_(D)=−112.9 (MeOH); Anal. Calc'd for C₁₉H₂₈N₂O₃: C,68.65;H, 8.49; N, 8.43. Found: C, 68.41; H, 8.11; N, 8.53.

The Boc group was removed from the compound of Preparation 3A (1.0 g,3.01 mmol) by dissolving in 2 mL of methylene chloride and added 2 mL oftrifluoroacetic acid. After stirring 1 h at room temperature thereaction was concentrated in vacuo (3×CH₂Cl₂). The compound was vacuumdried to 1.4 g (100%) of the ditrifluoroacetic acid salt. ¹H-NMR (d,CDCl₃, 400 MHz, equal intensity rotamers present at room temperature)0.01 (m, 0.5H), 0.70 (d, J=7.5 Hz, 1.5 H), 0.83 (m, 0.5H), 0.88 (d,J=7.5 Hz, 1.5 H), 1.00-1.60 (m, 4H), 2.55 (m, 1H), 2.90 (m, 1H), 3.52(m, 1H), 4.35 (m, 1H), 5.42 (m, 1H), 7.32-7.43 (m, 5H), 8.18 (br s, 2H),9.30 (br s, 2H); MS (ion spray) 233.1 (M+1);[α]_(D)=−38.1 (MeOH).

The amine from Preparation 3B (1.4 g, 3.04 mmol) was dissolved in 10 mLmethanol and 10 mL water and cooled to 0° C. Sodium bicarbonate (0.51 g,6.08 mmol) was added and stirred 10 min followed by the addition of1,4-dinitroimidazole. The solution quickly turned bright yellow andafter stirring 30 min the ice bath was removed and stirring continuedovernight at ambient temperature. The product was extracted into CH₂Cl₂,dried over sodium sulfate, filtered, and concentrated to 0.93 g of acrude yellow foam. A pure sample is obtained by crystallization fromEtOAc (0.60 g, 60%). ¹H-NMR (d, CDCl₃, 400 MHz, rotamers present) 0.05(m, 0.5H), 0.59 (d, J=7.5 Hz, 1.5 H), 0.72 (d, J=7.5 Hz, 1.5 H), 0.79(m, 0.5H), 0.93 (m, 0.5H), 1.14 (m, 0.5H), 1.23-1.56 (m, 3H), 2.44 (m,1H), 2.82 (m, 1H), 3.36 (m, 1H), 4.37 (m, 1H), 5.88 (s, 0.5H), 5.90 (s,0.5H), 7.02 (s, 1H), 7.10-7.30 (m, 5H), 7.52 (s, 1H); MS (ion spray)329.2 (M+1); [α]_(D)=−175.7 (MeOH); 96% ee by chiral HPLC; Anal. Calc'dfor C₁₇H₂₀N₄O₃: C, 62.18;H, 6.14; N, 17.06. Found: C, 62.93; H, 6.14; N,17.21.

Example 4 Chiral Synthesis of Nitroimidazole (D-isomer)

D-(p-hydroxyphenyl)glycine was Boc protected following the procedure ofSalituro, JACS, 760 (1990).

Example 4B

To a 0° C. solution of the phenol compound from Preparation 4A (3.0 g,11.2 mmol) in 100 mL of DMF was added 1.03 g (60% dispersion, 25.8 mmol)NaH. The mixture was then sonicated at room temperature for 30 min andmethyl iodide added (0.77 mL, 12.3 mmol) . The reaction becomes nearhomogenous after an additional 30 min of sonication. An additional 0.2mL of methyl iodide was added and the reaction stirred overnight at roomtemperature. The reaction was diluted with EtOAc and a few drops ofwater. The reaction was transferred to a separatory funnel and acidifiedwith a 10% sodium bisulfate solution and brine. The organic layer wasseparated and dried with sodium sulfate to 3.4 g of a crude yellow oil.This oil was purified by radial chromatography eluting with 80/20/5CH₂Cl₂/MeOH/NH₄OH. The appropriate fractions were taken up in EtOAc andwashed with 10% sodium bisulfate/brine solution, dried over sodiumsulfate, filtered and concentrated to 1.5 g (48%) of the desired ether.¹H-NMR (d, CDCl₃, 400 MHz, equal intensity rotamers present) 1.22 (s,4.5H), 1.40 (s, 4.5 H), 3.77 (s, 3H), 5.02 (d, J=5 Hz, 0.5 H), 5.22 (d,J=5 Hz, 0.5H), 5.39 (d, J=5 Hz, 0.5H), 6.82 (m, 2H), 7.29 (m, 2H), 7.62(m, 0.5H); MS (ion spray) 280.2 (M−1); [α]_(D)=−134.1 (MeOH); Anal.Calc'd for C₁₄H₁₉NO₅: C, 59.78;H, 6.81; N, 4.98. Found: C, 60.07; H,7.01; N, 4.99.

To a 0° C. solution of the acid from Preparation 4B (540 mg, 1.92 mmol)and dimethylamine hydrochloride (157 mg, 1.92 mmol) in 8 mL of anhydrousDMF was added diethylcyanophosphonate (DECP)(0.29 mL, 1.92 mmol) andtriethylamine (0.27 mL, 1.92 mmol). After 30 min at 0° C. a secondequivalent of dimethylamine hydrochloride, DECP, and triethylamine wereadded. After an additional 30 min the reaction was complete by TLC. Thereaction was diluted with EtOAc , washed with 1:1 10% sodiumbisulfate:brine, 1:1 10% sodium bicarbonate:brine, and brine. Theorganic layer was dried over sodium sulfate, filtered and concentratedto 0.90 g of a light yellow oil. This material was purified by radialchromatography eluting with 1:1 EtOAc:Hexanes. The appropriate fractionswere vacuum dried to 0.50 g (85%) of a white solid. ¹H-NMR (d, CDCl₃,400 MHz) 1.40 (s, 9H), 2.85 (s, 3H), 2.95 (s, 3H), 3.79 (s, 3H), 5.50(d, J=10 Hz, 1H), 5.96 (d, J=10 Hz, 1H), 6.83 (d, J=10 Hz, 2H), 7.29 (d,J=10 Hz, 2H); MS (ion spray) 309.3 (M+1); [α]_(D)=−165.5 (MeOH).

The Boc group was removed from the compound of Preparation 4C (450 mg,1.46 mmol) by dissolving in 2 mL of methylene chloride and added 2 mL oftrifluoroacetic acid. After stirring 90 min at room temperature thereaction was complete by TLC and HPLC and concentrated in vacuo(3×CH₂Cl₂). The compound was vacuum dried to 620 mg (97%) of theditrifluoroacetic acid salt. This material was used without furthercharacterization.

The amine from Preparation 4E (637 mg, 1.46 mmol) was dissolved in 10 mLmethanol and 10 mL water and cooled to 0° C. Sodium bicarbonate (270 mg,3.21 mmol) was added and stirred 10 min followed by the addition of1,4-dinitroimidazole. The solution quickly turned bright yellow andafter stirring 30 min the ice bath was removed and stirring continued 6h. The product was extracted into CH₂Cl₂, washed with brine, dried oversodium sulfate, filtered, and concentrated to 450 mg of a crude yellowoil. The compound was purified by radial chromatography eluting withEtOAc. The appropriate fractions were dried to 410 mg (92%) of a lightyellow solid. ¹H-NMR (d, CDCl₃, 400 MHz) 2.88 (s, 3H), 3.01 (s, 3H),3.80 (s, 3H), 6.01 (s, 1H), 6.94 (d, J=10 Hz, 2H), 7.29 (d, J=10 Hz,2H), 7.37 (s, 1H), 7.68 (s, 1H); MS (ion spray) 305.2 (M+1);[α]_(D)=−258.2 55.26;H, 5.30; N, 18.41. Found: C, 55.23; H, 5.27; N,18.23.

Example 5 Alternate Chiral Synthesis of Nitroimidazole-D-isomer)

D-Phenylglycine (400 mg, 2.53 mmol) was suspended in 5 mL methanol and 5mL water and cooled to 0° C. Sodium bicarbonate (400 mg, 5.06 mmol) wasadded and stirred 10 min followed by the addition of1,4-dinitroimidazole. The solution quickly turned bright yellow andafter stirring 30 min the ice bath was removed and stirring continuedovernight at ambient temperature. The reaction was diluted with EtOAcand acidified with 0.2N HCl. The organic extract was washed with brineand dried over sodium sulfate. Filtered, and concentrated to 620 mg(99%) of a light yellow solid. ¹H-NMR (d, DMSO, 400 MHz) 6.50 (s, 1H),7.42 (m, 3H), 7.52 (m, 2H), 7.94 (s, 1H), 8.40 (s ,1H); MS (ion spray)248.4 (M+1); [α]_(D)=−146.2 (MeOH); Anal. Calc'd for C₁₁H₉N₃O₄.0.3 H₂O:C, 52.30;H, 3.83; N, 16.63. Found: C, 52.17; H, 3.95; N, 16.79.

The acid from Preparation 5A (215 mg, 0.87 mmol) was dissolved in 10 mLanhydrous THF and cooled to 0° C. Added 4-methylpiperidine (103 μL, 0.87mmol), and diethylcyanophosphonate (DECP) (132 μL, 0.87 mmol). After 45min a second equivalent of 4-methylpiperidine and DECP were added andstirring continued at 0° C. for an additional 45 min. Diluted thereaction with ethyl acetate (300 mL) and washed with aqueous 10%NaHSO₄/brine, 5% NaHCO₃/brine, brine (150 mL each) and dried over NaSO₄.Purified by radial chromatography eluting with EtOAc which gave 236 mg(83%) of the desired product as a yellow oil. An analytical sample wasobtained by crystallization from EtOAc. ¹H-NMR (d, DMSO, 400 MHz,rotamers present) −0.05 (m, 0.5H), 0.68 (d, J=7.5 Hz, 1.5 H), 0.80 (m,0.5H), 0.83 (d, J=7.5 Hz, 1.5 H), 0.97 (m, 0.5H), 1.18 (m, 0.5H),1.40-1.60 (m, 3H), 2.60 (m, 1H) , 2.98 (m, 1H), 3.59 (m, 1H), 4.34 (m,1H), 6.85 (s, 0.5H), 6.92 (s, 0.5H), 7.37-7.50 (m, 5H), 7.78 (s, 1H),8.12 (s, 0.5H), 8.15 (s, 0.5H); MS (ion spray) 329.2 (M+1);[α]_(D)=−204.7 (MeOH); Anal. Calc'd for C₁₇H₂₀N₄O₃: C, 62.18;H, 6.14; N,17.06. Found: C, 62.47; H, 6.21; N, 17.07.

EXAMPLES PART 7

Melting points were determined with a Thomas-Hoover capillary meltingpoint apparatus and are uncorrected. Nuclear magnetic resonance studieswere performed on a Bruker ARX 500 spectrometer. Merck silica gel 60F254 plates (0.25 mm) were used for thin layer chromatography. Mercksilica gel 60 230-400 mesh was used for flash chromatography. BiotageKP-SIL, 60A cartridges were used for Biotage Flash 40 purifications.HPLC conditions: Eluent: 0.1% trifluoroacetic acid in water:acetonitrileat 2 mL/min. Column: Zorbax RX-C8. Detection: 230 nm.

Preparation 1 Ethyl 2-(2-Naphthyl)acetate

A steady stream of anhydrous hydrochloric acid was bubbled subsurfaceinto a solution of 2-naphthylacetic acid (251.38 grams, 1.35 mol)dissolved in ethanol (1760 mL) over a period of 10 minutes. Theresulting solution was stirred at ambient temperature until complete asdetermined by hplc (2 hours). The reaction mixture was concentrated todryness. The resulting oil was dissolved in ethyl acetate (200 mL) andfiltered through silica gel (300 grams) eluting the product with ethylacetate (1400 mL). The filtrate was concentrated to give 286.33 grams(99%) of ethyl 2-(2-naphthyl)acetate as a colorless oil. MS (FIA) m/z215.3 [(M+H)⁺]. ¹H nmr (DMSO-d₆): δ1.15-1.24 (t, 3H), 3.81-3.86 (d, 2H),4.07-4.15 (q, 2H), 7.41-7.55 (m, 3H), 7.80-7.92 (m, 4H).

Preparation 2 Ethyl 2-Bromo-2-(2-naphthyl)acetate

A solution consisting of ethyl 2-(2-naphthyl)acetate (1.07 grams, 5.0mmol), N-bromosuccinimide (0.89 grams, 5.0 mmol), benzoyl peroxide (0.05grams), and carbon tetrachloride (50 mL) was heated at reflux untilcomplete as determined by hplc (3 hours). The reaction was cooled toambient temperature, washed with water (2×25 mL), dried using sodiumsulfate, and filtered. The filtrate was concentrated to dryness. Theresidue was purified using a Biotage Flash 40M system eluting withhexane:ethyl acetate (49:1) to give 1.20 grams (82%) of ethyl2-bromo-2-(2-naphthyl) acetate, mp 80-82° C. MS (FIA) m/z 293.0[(M+H)⁺]. Anal. calcd. for C₁₄H₁₃O₂Br: C: 57.36; H: 4.47. Found: C:57.62; H: 4.54. ¹H nmr (CDCl₃): δ1.27-1.33 (t, 3H), 4.18-4.36 (m, 2H),5.56 (s, 1H), 7.52-7.55 (m, 2H), 7.71-7.76 (m, 1H), 7.82-7.92 (mn, 3H),7.97 (s, 1H).

Preparation 3 Ethyl 2-(2-Naphthyl)-2-(4-nitroimidazolyl)acetate

A yellow slurry consisting of ethyl 2-bromo-2-(2-naphthyl) acetate(384.04 grams, 1.31 mol), 4-nitroimidazole (148.13 grams, 1.31 mol),potassium carbonate (362.11 grams, 2.62 mol), and dimethyl formamide(2500 mL) was stirred at ambient temperature until complete asdetermined by hplc (16 hours). The reaction mixture was diluted withwater (2000 mL) and extracted with ethyl acetate (4×500 mL). The organicextracts were combined and washed with saturated sodium bicarbonatesolution (2×500 mL), 10% citric acid solution (2×500 mL), saturatedsodium chloride solution (2×500 mL), dried using sodium sulfate, andevaporated. A portion (50 grams) of the crude product was purified bycolumn chromatography on silica gel eluting with dichloromethane:heptane(16:3) gradient to dichloromethane:heptane:methanol (16:3:0.2) giving30.99 grams of ethyl 2-(2-naphthyl)-2-(4-nitroimidazolyl)acetate whichwas 90% pure by hplc. A 1 gram sample of the product was purified asecond time using a Biotage Flash 40S system eluting withdichloromethane:heptane:methanol (16.9:3:0.1) to give 0.90 grams (46%)of ethyl 2-(2-naphthyl)-2-(4-nitroimidazolyl)acetate as a tan oil. MS(FIA) m/z 326.4 [(M+H)⁺]. ¹H nmr (CDCl₃): δ1.25-1.31 (t, 3H), 4.28-4.39(m, 2H), 6.16 (s, 1H), 7.36-7.44 (dd, 1H), 7.54-7.62 (m, 3H), 7.84-7.90(m, 3H), 7.90-7.95 (m, 2H).

Preparation 3 Ethyl2-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetate

A mixture of ethyl 2-(2-naphthyl)-2-(4-nitroimidazolyl) acetate (2.04grams, 6.27 mmol), tetrahydrofuran (20 mL), and 10% palladium on carbon(2.04 gram) was hydrogenated at ambient temperature and pressure untilcomplete as determined by hplc (20 hours). The catalyst was removed byfiltration and rinsed with tetrahydrofuran (10 mL). The filtrate wasadded to a slurry consisting of 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.20 grams, 6.27 mmol),tetrahydrofuran (10 mL), and(2R)-2-{(2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoicacid (2.44 grams, 6.27 mmol) and stirred 16 hours at ambienttemperature. The reaction mixture was partitioned between water (150 mL)and ethyl acetate (3×50 mL). The organic extracts were combined, washedwith saturated sodium chloride solution, dried using sodium sulfate, andevaporated. The resulting crude oil was purified by columnchromatography on silica gel with hexane:ethyl acetate:methanol(10:10:1) as an eluent giving 1.72 grams (41%) of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetate. A 0.2 gram sample was furtherpurified using preparative reverse phase hplc to give 0.16 grams ofethyl 2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetate for analytical study. MS (FIA)m/z 667.4 [(M+H)⁺]. Anal. calcd. exact mass for C₃₇H₄₃N₆O₆[(M+H)⁺]=667.3244. Exact mass found by mass spectrometry: C₃₇H₄₃N₆O₆[(M+H)⁺]=667.3254. ¹H nmr (CDCl₃) 1.25-1.42 (m, 19H), 3.24-3.33 (m, 2H),4.28-4.33 (m, 2H), 4.98-5.01 (m, 1H), 5.94 (s, 1H), 6.85-7.01 (m, 3H),7.18-7.21 (m, 2H), 7.35-7.39 (m, 2H), 7.49-7.58 (m, 4H), 7.78-7.84 (m,4H), 8.69 (s, 1H), 10.65 (s, broad, 1H).

Preparation 4 Ethyl2-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-phenylacetate

This compound was obtained from the reduction of ethyl2-(4-nitroimidazolyl)-2-phenylacetate and subsequent reaction with(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indole-3-ylpropanoic acid as a yellow foam in 73%yield after purification by flash chromatography usingdichloromethane:methanol (19:1) as the eluent. MS (FIA) m/z 617.5[(M+H)⁺]. ¹H nmr (CDCl₃): δ1.19-1.32 (m, 18H), 3.10-3.12 (m, 1H),3.16-3.17 (m, 1H), 3.32 (s, 1H), 4.22-4.27 (m, 2H), 4.69 (s, broad, 1H),6.44 (s, 1H), 6.85-6.91 (m, 2H), 7.00 (t, 1H), 7.07-7.08 (m, 1H),7.38-7.40 (m, 1H), 7.42-7.45 (m, 6H), 7.55-7.56 (m, 2H), 10.16 (s,broad, 1H), 10.75 (s, 1H).

Preparation 5 Ethyl2-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-cyclohexylpropanoylamino)imidazolyl]-2-phenylacetate

This compound was obtained from the reduction of ethyl2-(4-nitroimidazolyl)-2-phenylacetate and subsequent reaction with(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-cyclohexylpropanoic acid as a yellow foam in 45% yieldafter after purification by flash chromatography usingdichloromethane:methanol (29:1) as the eluent. ¹H nmr (CDCl₃):δ0.77-0.99 (m, 4H), 1.00-1.21 (m, 5H), 1.22-1.27 (m, 7H), 1.33-1.45 (m,8H), 1.48-1.74 (m, 6H), 4.19-4.30 (m, 2H), 4.70-4.75 (m, 1H), 5.10 (s,broad, 1H), 5.84-5.86 (t, 1H), 6.92 (s, broad, 1H), 7.25-7.41 (m, 7H),7.51 (m, 1H), 10.5 (s, broad, 1H).

Preparation 6 Ethyl2-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}pentanoylamino)imidazolyl]-2-phenylacetate

This compound was obtained from the reduction of ethyl2-(4-nitroimidazolyl)-2-phenylacetate and subsequent reaction with(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methyl propanoylamino}pentanoicacid as a yellow foam in 61% yield after purification using preparativereverse phase hplc. MS (FD+) m/z 529 (M⁺). ¹H nmr (CDCl₃): δ0.82-0.84(m, 3H), 1.25-1.46 (m, 20H), 1.60-1.75 (m, 1H), 1.77-1.83 (m, 1H),4.24-4.32 (m, 2H), 4.76-4.78 (m, 1H), 5.25 (s, broad, 1H), 5.93-5.96 (m,1H), 7.15-7.30 (m, 1H), 7.36-7.39 (m, 5H), 7.48-7.49 (m, 1H), 7.61-7.64(d, 1H), 11.10-11.20 (m, 1H).

Preparation 7 Ethyl2-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}hexanoylamino)imidazolyl]-2-phenylacetate

This compound was obtained from the reduction of ethyl2-(4-nitroimidazolyl)-2-phenylacetate and subsequent reaction with(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methyl propanoylamino}hexanoicacid as a yellow foam in 74% yield after purification by flashchromatography using dichloromethane:methanol (19:1) as the eluent. ¹Hnmr (CDCl₃): δ0.87-0.88 (d, 3H), 1.28-1.32 (m, 7H), 1.44-1.46 (m, 8H),1.51 (s, 6H), 1.66-1.68 (m, 3H), 1.95 (s, broad, 1H), 4.28-4.34 (m, 2H),4.60-4.62 (m, 1H), 5.05 (s, broad, 1H), 5.85 (s, 1H), 6.90-7.00 (m, 1H),7.36-7.46 (m, 6H), 9.65 (s, broad, 1H).

Preparation 8 Ethyl2-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-(3-thienyl)propanoylamino)imidazolyl]-2-phenylacetate

This compound was obtained from the reduction of ethyl2-(4-nitroimidazolyl)-2-phenylacetate and subsequent reaction with(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-(3-thienyl)propanoic acid as a yellow foam in 53%yield after purification using preparative reverse phase hplc. MS (FD+)m/z 583 (M⁺). Anal. calcd. for C₂₉H₃₇N₅O₆.1/2H₂O: C, 58.77; H, 6.46; N,11.82. Found: C, 58.83; H, 6.03; N, 11.83. ¹H nmr (CDCl₃): δ1.20-1.23(m, 3H), 1.33 (s, 9H), 1.40 (s, 6H), 3.29-3.30 (d, 2H), 4.18-4.27 (m,2H), 5.04 (s, broad, 1H), 5.40 (s, broad, 1H), 5.94 (s, broad, 1H),6.72-6.76 (m, 2H), 6.96-6.98 (t, 1H), 7.34 (s, 5H), 7.48 (s, 2H),7.54-7.62 (m, 1H), 11.38 (m, 1H).

Preparation 9 Ethyl2-[4-((2R)-3-Benzo[b]thiophen-3-yl-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}propanoylamino)imidazolyl]-2-phenylacetate

This compound was obtained from the reduction of ethyl2-(4-nitroimidazolyl)-2-phenylacetate and subsequent reaction with(2R)-3-benzo[b]thiophen-3-yl-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}propanoicacid as a yellow foam in 82% yield. ¹H nmr (CDCl₃): δ1.26-1.46 (m, 18H),3.34-3.35 (m, 1H), 3.55-3.56 (m, 1H), 4.26-4.33 (m, 2H), 5.15 (s, broad,2H), 5.82-5.84 (t, 1H), 7.20-7.47 (m, 10H), 7.60-7.65 (m 0.5H),7.72-7.73 (m, 1H), 8.11-8.12 (m, 0.5H), 11.10 (m, broad, 1H). ¹³C nmr(CDCl₃): δ14.46, 14.60, 19.34, 21.42, 25.69, 28.62, 36.64, 53.29, 54.39,57.01, 60.77, 62.67, 64.05, 108.00, 122.26, 124.23, 124.34, 124.51,125.58, 125.60, 125.87, 126.37, 127.92, 128.18, 128.24, 128.28, 128.35,128.94, 129.58, 129.64, 129.68, 134.11, 134.53, 137.61, 140.55, 168.81,168.86, 171.51, 174.81.

Preparation 102-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)aceticAcid

A solution consisting of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetate(1.52 grams, 2.28 mmol), lithium hydroxide (0.11 grams, 4.56 mmol),dioxane (10 mL), and water (10 mL) was stirred at ambient temperatureuntil complete as determined by hplc (30 minutes). The reaction mixturewas concentrated to dryness and the residue was dissolved in water (20mL). The aqueous solution was adjusted to a pH of 3 using a 10% sodiumbisulfate solution and extracted with ethyl acetate (3×25 mL). Theorganic layers were combined, dried using sodium sulfate, filtered, andconcentrated to give 1.34 grams (92%) of2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)aceticacid.

Preparation 112-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-cyclohexylpropanoylamino)imidazolyl]-2-phenylaceticAcid

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-cyclohexylpropanoylamino)imidazolyl]-2-phenylacetateas a white powder in 69% yield. ¹H nmr (DMSO-d₆): δ0.64-0.92 (m, 3H),0.93-1.15 (m, 3H), 1.16-1.41 (m, 7H), 1.42-1.73 (m, 4H), 4.36 (s, broad,1H), 6.08 (s, 1H), 6.98 (s, 1H), 7.15 (s, 1H), 7.31 (s, 5H), 7.49 (s,2H), 10.0 (d, broad, 1H).

Preparation 122-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-(2-naphthyl)propanoylamino)imidazolyl]-2-phenylaceticAcid

This compound was obtained from the reduction of ethyl2-(4-nitroimidazolyl)-2-phenylacetate and subsequent reaction with(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-(2-naphthyl)propanoic acid followed by hydrolysis togive a white solid in 76% yield. ¹H nmr (DMSO-d₆) δ1.02-1.13 (t, 7H),1.27 (s, 8H), 3.24 (m, 3H), 3.50 (m, 1H), 4.58-4.78 (m, 1H), 6.24 (s,1H), 7.00 (s, broad, 1H), 7.13-7.56 (m, 9H), 7.73 (d, 1.5H), 7.84 (d,1.5H), 8.16 (m, 1H), 9.98 (s, broad, 0.5H), 10.11 (s, broad, 0.5H),13.51 (s, broad, 1H).

Preparation 13

N-[(1R)-2-Indol-3-yl-1-(N-{1-[2-(4-methylpiperidinyl)-1-(2-naphthyl)-2-oxoethyl]imidazol-4-yl}carbamoyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

A solution consisting of2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)aceticacid (0.55 grams, 0.861 mmol), 4-methylpiperidine (0.085 grams, 0.861mmol), 1,3-dicyclohexylcarbodiimide (0.195 grams, 0.947 mmol),1-hydroxybenzotriazole hydrate (0.116 grams, 0.861 mmol) and dimethylformamide (5 mL) was stirred at ambient temperature until complete asdetermined by hplc (7 hours). The reaction mixture was diluted withwater (40 mL) and extracted with ethyl acetate (4×25 mL). The organicextracts were combined, washed with saturated sodium chloride solution(2×35 mL), dried using sodium sulfate, and concentrated to an oil. Thecrude product was purified using preparative reverse phase hplc to give0.32 grams (52%) ofN-[(1R)-2-indol-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-1-(2-naphthyl)-2-oxoethyl]imidazol-4-yl}carbamoyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide.¹H nmr (CDCl₃): 0.76-0.77 (d, 2H), 0.91-0.95 (m, 2H), 1.23-1.36 (m,18H), 1.54 (m, 1H), 1.67 (m, 1H), 2.70-2.72 (m, 2H), 3.25-3.29 (m, 2H),3.68 (m, 1H), 4.55-4.70 (m, 1H), 4.98 (m, 1H), 6.24 (m, 1H), 6.81-6.83(d, 1H), 6.92 (m, 1H), 7.00-7.01 (m, 1H), 7.18-7.28 (m, 3H), 7.37-7.55(m, 5H), 7.76-7.83 (m, 4H), 8.80 (s, broad, 1H), 10.38 (s, broad, 1H).¹³C nmr (CDCl₃): δ14.60, 19.32, 19.47, 21.41, 21.83, 21.90, 25.39,25.55, 26.04, 28.56, 28.63, 28.84, 31.05, 31.16, 31.21, 33.98, 34.08,34.29, 34.69, 43.42, 46.28, 46.52, 49.38, 54.55, 56.99, 60.77, 62.31,69.97, 71.02, 108.80, 110.24, 111.79, 119.02, 119.36, 121.86, 124.10,125.99, 127.12, 127.36, 127.97, 128.08, 128.10, 128.16, 128.33, 128.63,128.71, 129.77, 132.26, 133.63, 133.75, 134.02, 136.58, 137.29, 155.16,157.65, 166.07, 166.18, 166.22, 166.34, 169.40, 171.52, 175.12.

Preparation 14N-[(1R)-2-Indol-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with 4-methylpiperidine in 84% yield afterBiotage Flash 40M purification using dichloromethane:methanol (24:1) asthe eluent. MS (FIA) m/z 670.5 [(M+H)^(+].) ¹H nmr (CDCl₃): δ0.74-0.75(d, 2H), 0.89-0.90 (d, 2H), 1.17-1.32(m, 18H), 1.53-1.63 (m, 3H),2.66-2.70 (m, 1H), 3.05 (t, 1H), 3.15-3.20 (m, 1H), 3.69-3.83 (m, 1H),4.36-4.49 (m, 1H), 4.67 (s, broad, 1H), 6.90-6.93 (m, 2H), 7.01-7.04 (m,2H), 7.11 (s, 1H), 7.26-7.32 (m, 2H), 7.40-7.54 (m, 5H), 7.67 (s, broad,1H), 8.16 (m, broad, 1H), 10.49 (s, broad, 1H), 10.84 (s, 1H).

Preparation 15N-((1R)-2-Indol-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with pyrrolidine in 80% yield after purificationby flash chromatography using dichloromethane:methanol (19:1) as theeluent. ¹H nmr (CDCl₃): δ1.10-1.40 (m, 15H), 1.67-1.92 (m, 3H),2.92-3.60 (m, 5H), 4.90 (s, broad, 1H), 5.33 (s, broad, 1H), 5.85 (d,1H), 6.80-7.05 (m, 3H), 7.13-7.39 (m, 10H), 7.44-7.80 (m, 2H), 8.96 (s,broad, 1H), 10.20 (s, broad, 1H). ¹³C nmr (CDCl₃): δ14.25, 21.11, 24.02,25.63, 26.08, 28.24, 33.87, 46.39, 46.64, 54.28, 56.67, 60.46, 63.07,63.09, 108.33, 109.73, 110.69, 111.47, 118.36, 118.56, 119.05, 121.57,123.77, 125.01, 126.42, 127.60, 128.51, 129.38, 133.14, 133.85, 136.23,136.45, 136.49, 165.79, 165.85, 169.17, 174.87.

Preparation 16N-((1R)-2-Cyclohexyl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

This compound was obtained from the reaction of2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-cyclohexylpropanoylamino)imidazolyl]-2-phenylaceticacid and pyrrolidine in 99% yield after purification by flashchromatography using dichloromethane:methanol (19:1) as the eluent. ¹Hnmr (CDCl₃): δ0.71-1.00 (m, 2H), 1.00-1.16 (m, 2H), 1.17-2.18 (m, 28H),3.07-3.20 (s, broad, 1H), 3.38-3.64 (m, 3H), 4.62-4.77 (m, 1H), 5.91 (t,1H), 7.38 (m, 7H), 9.93 (s, broad, 1H), 10.60 (s, broad, 1H).

Preparation 17 Methyl1-{2-[4-((2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-cyclohexylpropanoylamino)imidazolyl]-2-phenylacetyl}(2S)pyrrolidine-2-carboxylate

This compound was obtained from the reaction of2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-cyclohexylpropanoylamino)imidazolyl]-2-phenylaceticacid and L-proline methyl ester in 88% yield after purification by flashchromatography using dichloromethane:methanol (19:1) as the eluent. ¹Hnmr (CDCl₃): δ0.75-0.98 (m, 4H), 0.98-1.21 (m, 4H), 1.21-1.50 (m, 12H),1.50-1.80 (m, 5H), 1.80-2.07 (m, 3H), 2.07-2.28 (m, 1H), 3.19-3.36 (m,1H), 3.37-3.72 (m, 2H), 3.72 (s, 3H), 4.03-4.61 (m, 1H), 4.61-4.75 (m,1H), 5.11 (s, broad, 1H), 5.92-6.00 (m, 1H), 7.00 (s, broad, 1H),7.21-7.49 (m, 7H), 8.00 (s, 1H), 9.60 (s, broad, 1H).

Preparation 18(2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]pentanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}pentanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with pyrrolidine in 87% yield after purificationby preparative reverse phase hplc. ¹H nmr (CDCl₃): δ0.72-0.75 (m, 3H),1.18-1.41 (m, 17H), 1.75-1.79 (m, 4H), 1.80-1.92 (m, 1H), 3.00 (s,broad, 1H), 3.09-3.11 (m, 1H), 3.44-3.52 (m, 3H), 4.74 (m, 1H), 5.45 (s,broad, 1H), 6.09-6.10 (d, 1H), 7.28-7.52 (m, 8H), 10.98-11.07 (m, 1H).¹³C nmr (CDCl₃): δ14.14, 14.54, 18.95, 21.36, 24.35, 24.88, 26.43,26.49, 26.54, 28.65, 35.62, 35.68, 46.72, 46.86, 53.55, 56.85, 60.70,63.31, 108.46, 128.86, 129.46, 129.59, 133.70, 134.69, 134.74, 137.31,166.20, 166.26, 170.06, 171.46, 175.02.

Preparation 19(2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}pentanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}pentanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with 4-methylpiperidine in 72% yield afterpurification by preparative reverse phase hplc. ¹H nmr (CDCl₃):δ0.30-0.40 (m, 0.5H), 0.77-0.80 (m, 4H), 0.91-0.92 (d, 1H), 1.05-1.20(m, 0.5H), 1.23-1.56 (m, 23H), 1.62-1.67 (m, 1H), 1.76 (s, broad, 1H),2.59-2.72 (m, 1.5H), 3.00 (t, 0.5H), 3.71 (m, 1H), 4.53-4.61 (dd, 1H),4.73 (s, broad, 1H), 5.40 (s, broad, 1H), 6.26-6.32 (m, 1H), 7.29-7.45(m, 7H), 10.89-10.93 (m, 1H). ¹³C nmr (CDCl₃): δ14.15, 14.16, 14.56,18.97, 21.82, 21.93, 24.90, 25.39, 26.01, 26.50, 26.55, 28.69, 31.12,31.20, 33.93, 34.25, 34.70, 35.53, 35.64, 43.35, 46.31, 46.42, 53.63,53.85, 56.90, 60.74, 62.23, 62.32, 108.61, 128.65, 128.93, 129.47,129.60, 129.70, 134.01, 134.97, 137.16, 137.24, 165.99, 166.06, 166.12,166.21, 170.04, 175.05.

Preparation 20 (2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]hexanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}hexanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with pyrrolidine in 63% yield after purificationby preparative reverse phase hplc. ¹H nmr (CDCl₃): δ0.68-0.71 (m, 3H),1.20-1.22 (m, 5H), 1.33 (s, 11H), 1.41 (s, 3H), 1.68 (m, 1H), 1.74-1.78(m, 4H), 1.86-1.88 (m, 1H), 3.08-3.09 (m, 1H), 3.44-3.51 (m, 3H), 4.74(s, broad, 1H), 5.50 (s, broad, 1H), 6.09-6.10 (d, 1H), 7.27-7.33 (m,3H), 7.37-7.39 (m, 2H), 7.45-7.57 (m, 3H), 11.05-11.06 (m, 1H). ¹³C nmr(CDCl₃): δ14.11, 19.35, 22.73, 24.35, 26.42, 26.46, 26.51, 27.65, 28.68,31.15, 33.22, 33.30, 46.72, 46.84, 53.72, 56.84, 63.27, 69.71, 108.47,128.84, 129.43, 129.57, 133.68, 133.76, 134.74, 134.80, 137.30, 166.19,166.26, 170.11, 175.01.

Preparation 21(2R)-2-{2-[(Tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}hexanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}hexanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with 4-methylpiperidine in 66% yield afterpurification by preparative reverse phase hplc. ¹H nmr (CDCl₃):δ0.73-0.74 (m, 3H) , 0.89-0.91 (m, 1H), 1.21-1.66 (m, 28H), 1.75-1.87(m, 1H), 2.57-2.63 (q, 1H), 2.72 (t, 0.5H), 2.99 (t, 0.5H), 3.70-3.72(m, 1H), 4.53-4.61 (dd, 1H), 4.73 (s, broad, 1H), 5.43 (s, broad, 1H),6.28-6.31 (d, 1H), 7.33-7.50 (m, 7H), 11.01-11.03 (m, 1H). ¹³C nmr(CDCl₃): δ14.15, 14.55, 19.34, 21.39, 21.83, 21.93, 22.76, 25.40, 26.49,26.56, 27.63, 28.70, 28.73, 31.12, 31.21, 33.24, 33.33, 33.94, 34.24,34.70, 43.32, 46.30, 46.41, 53.72, 56.88, 60.72, 62.10, 62.17, 62.26,108.57, 128.64, 128.92, 129.42, 129.56, 129.67, 133.84, 135.00, 135.04,135.07, 137.20, 137.25, 137.28, 137.32, 165.97, 166.02, 166.12, 166.18,170.00, 174.95.

Preparation 22N-[(1R)-1-(N-{1-[2-(4-Methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)-2-(3-thienyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-(3-thienyl)propanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with 4-methylpiperidine in 70% yield afterpurification by preparative reverse phase hplc. ¹H nmr (CDCl₃):δ0.79-0.80 (d, 2H), 0.91-0.92 (m, 2H), 0.93-1.15 (m, 3H), 1.32-1.40 (m,15H), 1.45-1.55 (m, 1H), 1.64 (m, 1H), 2.60-2.62 (m, 1H), 2.75 (t,0.5H), 2.98 (t, 0.5H), 3.32-3.35 (d, 2H), 3.70 (m, 1H), 4.50-4.67 (dd,1H), 5.00 (m, 1H), 5.50 (s, broad, 1H), 6.23-6.24 (m, 1H), 6.73-6.76 (m,2H), 6.97-6.98 (m, 1H), 7.32-7.45 (m, 6H), 7.56 (s, broad, 1H), 10.94(s, broad, 1H). ¹³C nmr (CDCl₃): δ14.58, 19.45, 21.40, 21.95, 25.58,25.62, 25.69, 28.75, 31.12, 33.15, 33.94, 33.98, 34.26, 43.36, 46.32,46.45, 49.28, 54.74, 56.97, 60.74, 62.17, 62.28, 69.84, 108.79, 124.54,126.95, 127.23, 128.60, 128.93, 129.60, 129.70, 134.03, 135.01, 135.14,137.05, 137.19, 138.80, 157.69, 165.97, 168.51, 171.49, 175.14.

Preparation 23N-((1R)-1-{N-[1-(2-Oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}-2-(3-thienyl)ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-2-{2-[(tert-butoxy)carbonylaminol]-2-methylpropanoylamino}-3-(3-thienyl)propanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with pyrrolidine in 71% yield after purificationby preparative reverse phase hplc. ¹H nmr (CDCl₃): δ1.32-1.39 (m, 15H),1.77-1.81 (m, 3H), 1.90 (m, 1H), 3.13 (m, broad, 1H), 3.35 (s, 2H),3.48-3.54 (m, 3H), 4.97-5.08 (m, 1H), 5.50 (s, broad, 1H), 6.03-6.05 (m,lH), 6.73-6.76 (m, 2H), 6.98-6.99 (m, 1H), 7.34-7.40 (m, 5H), 7.45-7.48(m, 2H), 10.91 (s, broad, 1H). ¹³C nmr (CDCl₃): δ14.58, 19.37, 21.41,24.39, 25.55, 25.60, 25.66, 26.46, 28.73, 31.19, 33.15, 46.76, 46.91,54.73, 56.98, 60.74, 63.36, 69.84, 108.56, 108.63, 124.56, 126.94,127.24, 128.79, 128.82, 128.87, 129.53, 129.65, 133.82, 134.70, 134.83,134.87, 137.14, 137.19, 137.24, 138.79, 166.11, 168.52, 171.50, 175.08.

Preparation 24N-((1R)-2-Benzo[b]thiophen-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-3-benzo[b]-thiophen-3-yl-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}propanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with pyrrolidine in 68% yield after purificationby preparative reverse phase hplc. ¹H nmr (CDCl₃): δ1.21-1.34 (m, 15H),1.76-1.87 (m, 3H), 3.00-3.10 (m, 1H), 3.34-3.38 (m, 2H), 3.48-3.57 (m,3H), 5.17 (s, 1H), 5.40 (s, broad, 1H), 5.92 (s, 1H), 7.16-7.30 (m, 1H),7.34 (s, 10H), 7.39-7.46 (m, 1H), 7.57-7.59 (m, 0.5H), 7.68-7.69 (m,1H), 8.06-8.07 (d, 0.5H), 10.85 (s, broad, 1H). ¹³C nmr (CDCl₃): δ14.58,19.38, 21.41, 24.38, 25.54, 25.64, 25.70, 26.03, 26.43, 28.58, 31.20,34.26, 36.36, 46.70, 46.90, 49.27, 53.40, 54.44, 56.93, 60.75, 63.23,69.80, 108.47, 108.61, 122.87, 124.29, 124.35, 124.44, 125.64, 125.84,126.45, 127.78, 128.17, 128.75, 128.79, 128.83, 129.51, 129.61, 132.48,133.42, 134.04, 134.78, 137.14, 139.34, 140.45, 157.71, 166.11, 168.93,171.51, 175.01, 175.13.

Preparation 25N-[(1R)-2-Benzo[b]thiophen-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

This compound was obtained from the hydrolysis of ethyl2-[4-((2R)-3-benzo[b]-thiophen-3-yl-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}propanoylamino)imidazolyl]-2-phenylacetateand subsequent reaction with 4-methylpiperidine in 71% yield afterpurification by preparative reverse phase hplc. ¹H nmr (CDCl₃):δ0.78-0.79 (d, 1H), 0.90-1.00 (d, 1H), 1.12-1.33 (m, 20H), 1.51 (m, 1H),1.64 (m, 1H), 2.61-2.67 (m, 1.5H), 2.90 (m, 1H), 3.32-3.33 (m, 1H),3.51-3.62 (m, 2.5H), 4.57-4.68 (m, 1H), 5.45 (s, 1H), 6.11-6.14 (s,broad, 1H), 7.19-7.45 (m, 10H), 7.57-7.59 (m, 0.5H), 7.67-7.69 (m, 1H),8.06 (s, broad, 0.5H), 11.00 (s, broad, 1H). ¹³C nmr (CDCl₃): δ14.59,19.41, 21.41, 21.86, 21.88, 21.98, 25.45, 25.69, 25.79, 26.04, 28.71,31.15, 32.10, 33.97, 34.26, 34.68, 36.40, 43.27, 46.27, 46.40, 49.24,53.42, 54.44, 56.90, 60.75, 62.13, 108.68, 108.81, 122.87, 124.28,124.35, 124.41, 125.64, 125.84, 126.45, 127.78, 128.20, 128.61, 128.85,129.47, 129.57, 129.66, 132.50, 133.40, 134.03, 135.05, 135.15, 139.38,140.44, 157.75, 165.86, 166.05, 169.02, 171.50, 174.98, 175.14.

Example 1N-[(1R)-2-Indol-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-1-(2-naphthyl)-2-oxoethyl]imidazol-4-yl}carbamoyl)ethyl]-2-amino-2-methylpropanamideDihydrochloride

A solution consisting ofN-[(1R)-2-indol-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-1-(2-naphthyl)-2-oxoethyl]imidazol-4-yl}carbamoyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide(0.32 grams, 0.445 mmol) and anisole (0.25 mL) dissolved in methylenechloride (20 mL) was added trifluoroacetic acid (2.5 mL). The resultingreaction mixture was stirred at ambient temperature until complete asdetermined by hplc (2.5 hours). The reaction mixture was concentrated todryness. The residue was dissolved in methanol (5 mL) and applied to aVarian Mega Bond Elut SCX ion exchange column (5 gram). The column waswashed with methanol (50 mL). The product was eluted from the columnwith 2N ammonia in methanol (30 mL). The eluent was concentrated todryness to give the free base (0.28 grams). A 1.95 M solution ofanhydrous HCl in ethyl acetate (0.456 mL, 0.89 mmol) was added to thefree base which was dissolved in ethyl acetate (10 mL). The resultingprecipitate was collected by filtration and dried in vacuum to give 0.27grams (87%) ofN-[(1R)-2-indol-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-1-(2-naphthyl)-2-oxoethyl]imidazol-4-yl}carbamoyl)ethyl]-2-amino]-2-methylpropanamidedihydrochloride. MS (FIA) m/z 620.7 [(M+H)⁺]. Anal. calcd. forC₃₆H₄₁N₇O₃.2HCl.1/2H₂O: C: 61.62; H: 6.32; N: 13.97.

Found: C: 61.42; H: 6.18; N: 13.62. Anal. calcd. exact mass forC₃₆H₄₂N₇O₃ [(M+H)^(+]=)620.3349. Exact mass found by mass spectrometry:C₃₆H₄₂N₇O₃ [(M+H)^(+]=)620.3355. ¹H nmr (DMSO-d₆): 0.65-0.67 (d, 2H),0.89-0.90 (d, 2H), 1.16-1.24 (m, 2H), 1.35-1.36 (d, 4H), 1.51-1.53 (d,4H), 1.63-1.65 (m, 1H), 2.68-2.74 (m, 1.5H), 3.08 (t, 0.5H), 3.17-3.19(m, 1H), 3.26-3.27 (m, 1H), 3.71-3.82 (m, 1H), 4.40-4.55 (m, 1H),4.71-4.72 (t, 1H), 6.90-7.00 (m, 1H), 7.02-7.04 (m, 1H), 7.26-7.33 (m,3H), 7.52 (m, 1H), 7.59-7.62 (m, 3H), 7.74 (m, 1H), 7.98-8.09 (m, 4H),8.31-8.32 (d, 3H), 8.49-8.61 (m, 1H), 8.66-8.68 (d, 1H), 10.94 (s, 1H),11.35 (s, 1H).

Example 2N-[(1R)-2-Indol-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)ethyl]-2-amino-2-methylpropanamide Dihydrochloride

This compound was obtained fromN-[(1R)-2-indol-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamideas a red foam in 100% yield. MS (FIA) m/z 570.5 [(M+H)⁺]. ¹H nmr(d-MeOH): δ0.81-0.82 (d, 2H), 0.98-0.99 (d, 2H), 1.18-1.21 (m, 2H),1.34-1.37 (m, 1H), 1.43 (s, 3H), 1.61 (s, 6H), 1.71 (t, 1H), 2.73-2.76(m, 1.5H), 3.14 (t, 0.5H), 3.27-3.33 (m, 1H), 3.40-3.44 (m, 1H),3.61-3.65 (m, 1H), 3.75-3.77 (d, 1H), 4.45-4.60 (m, 1H), 4.81 (s, broad,4H), 6.94-6.99 (m, 1.5H), 7.06-7.07 (m, 1.5H), 7.19 (s, 1H), 7.31-7.35(m, 2H), 7.52-7.61 (m, 6H), 8.62-8.65 (d, 1H).

Example 3N-((1R)-2-Indol-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-amino-2-methylpropanamideBistrifluoroacetic Acid

This compound was obtained fromN-((1R)-2-indol-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamideas a white solid in 50% yield. MS (FD+) m/z 541 (M⁺). Anal. calcd. forC₃₀H₃₅N₇O₃.2C₂HF₃O₂: C: 53.06; H: 4.85; N: 12.74. Found: C: 52.93; H:4.88; N: 12.55. ¹H nmr (DMSO-d₆): δ1.29 (s, 3H), 1.46-1.48 (d, 3H),1.72-1.88 (m, 4H), 2.94 (m, 1H), 3.06-3.07 (m, 1H), 3.19-3.20 (m, 1H),3.40-3.41 (d, 2H), 3.67-3.69 (m, 1H), 4.78 (s, broad, 1H), 6.53 (s, 1H),6.93-6.97 (m, 1H), 7.06 (m, 1H), 7.20 (d, 1H), 7.31-7.36 (m, 2H),7.42-7.42 (m, 4H), 7.73-7.80 (m, 2H), 8.01 (s, broad, 2H), 8.36-8.38 (d,1H), 10.82-10.85 (d, 2H).

Example 4 N-((1R)-2-Cyclohexyl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-amino-2-methyl propanamideBistrifluoroacetic Acid

This compound was obtained fromN-((1R)-2-cyclohexyl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide as a white solid in 81% yield. MS (FD+) m/z 508.2 (M⁺).Anal. calcd. for C₂₈H₄₀N₆O₃.2C₂HF₃O₂: C, 52.17; H, 5.75; N, 11.41.Found: C, 52.11; H, 5.81; N, 11.40. ¹H nmr (DMSO-d₆): δ0.91 (m, 2H),1.11-1.13 (m, 3H), 1.31 (s, broad, 1H), 1.48-1.79 (m, 18H), 2.91-2.93(m, 1H), 3.38 (m, 2H), 3.65-3.68 (m, 1H), 4.53-4.54 (m, 1H), 6.52 (s,1H), 7.30 (s, 1H), 7.41-7.48 (m, 5H), 7.77-7.81 (d, 1H), 8.13-8.14 (d,3H), 8.30-8.31 (d, 1H), 10.68 (s, 1H).

Example 5 Methyl1-(2-{4-[(2R)-2-(2-Amino-2-methylpropanoylamino)-3-cyclohexylpropanoylamino]imidazolyl}-2-phenylacetyl)(2S)pyrrolidine-2-carboxylate Bistrifluoroacetic Acid

This compound was obtained from methyl1-{2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-cyclohexylpropanoylamino)imidazolyl]-2-phenylacetyl}(2S)pyrrolidine-2-carboxylate as an off white solid in 53% yield. MS (FD+)m/z 566.2 (M⁺). Anal. calcd. for C₃₀ H₄₂N₆O₅.2C₂HF₃O₂: C, 51.38; H,5.58; N, 10.57. Found: C, 51.44; H, 5.59; N, 10.66. ¹H nmr (DMSO-d₆):δ0.91 (m, 2H), 1.12-1.16 (m, 3H), 1.30 (s, broad, 1H), 1.47-1.67 (m,13H), 1.81-1.87 (m, 3H), 2.10-2.30 (m, 1H), 2.95-3.15 (m, 1H), 3.64 (s,1H), 3.68 (s, 2H), 3.72-3.75 (m, 1H), 4.41-4.43 (t, 1H), 4.53-4.54 (m,1H), 6.59-6.62 (m, 1H), 7.17-7.19 (d, 0.5H), 7.37-7.47 (m, 6.5H),7.57-7.62 (d, 1H), 8.11 (s, broad, 3H), 8.25-8.28 (m, 1H), 10.55 (s,1H).

Example 6(2R)-2-(2-Amino-2-methylpropanoylamino)-N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]pentanamideBistrifluoroacetic Acid

This compound was obtained from(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]pentanamideas an off white solid in 82% yield. MS (FD+) m/z 454 (M⁺). Anal. calcd.for C₂₄H₃₄N₆O₃.2C₂HF₃O₂: C, 49.27; H: 5.32; N, 12.31. Found: C, 49.19;H, 5.29; N, 12.25. ¹H nmr (DMSO-d₆): δ0.88-0.90 (m, 3H), 1.20-1.30 (m,1H), 1.30-1.39 (m, 1H), 1.50-1.51 (m, 6H), 1.68-1.85 ((m, 7H), 2.89-2.90(m, 1H), 3.40 (s, broad, 2H), 3.67 (s, broad, 1H), 4.41-4.42 (m, 1H),6.59 (s, 1H), 7.35 (s, 1H), 7.44-7.46 (m, 5H), 7.96-8.00 (d, 1H),8.19-8.20 (m, 3H), 8.33-8.35 (d, 1H), 10.85 (s, 1H).

Example 7(2R)-2-(2-Amino-2-methylpropanoylamino)-N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}pentanamideBistrifluoroacetic Acid

This compound was obtained from(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}pentanamideas an off white solid in 85% yield. MS (FD+) m/z 482 (M⁺). Anal. calcd.for C₂₆H₃₈N₆O₃.2C₂HF₃O₂.1/2H₂O: C, 50.07; H, 5.74; N, 11.68. Found: C,49.94; H, 5.53; N, 11.51. ¹H nmr (DMSO-d₆): δ0.73-0.74 (d, 2H),0.86-0.89 (m, 7H), 0.95-1.69 (m, 12H), 2.61-2.68 (m, 2H), 3.02 (t, 1H),3.69-3.76 (t, 1H), 4.36-4.41 (m, 2H), 6.82-6.87 (d, 1H), 7.29 (s, 1H),7.37-7.49 (m, 5H), 7.86-7.91 (m, 1H), 8.17-8.19 (d, 3H), 8.32-8.33 (d,1H), 10.79 (s, 1H).

Example 8 (2R)-2-(2-Amino-2-methylpropanoylamino)-N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}hexanamideBistrifluoroacetic Acid

This compound was obtained from(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}hexanamideas an off white solid in 90% yield. MS (FD+) m/z 496.3 (M⁺). Anal.calcd. for C₂₇H₄₀N₆O₃.2C₂HF₃O₂: C, 51.38; H, 5.84; N, 11.60. Found: C,51.38; H, 5.83; N, 11.59. ¹H nmr (DMSO-d₆): δ0.73-0.74 (d, 2H),0.84-0.89 (m, 5H), 1.00-1.28 (m, 1H), 1.28-1.30 (m, 5H), 1.49-1.69 (m,11H), 2.64-2.66 (m, 1.5H), 3.02 (t, 0.5H), 3.69-3.72 (t, 1H), 4.39-4.43(m, 2H), 6.82-6.84 (m, 1H), 7.28-7.30 (m, 1H), 7.38-7.49 (m, 5H),7.87-7.90 (m, 1H), 8.16-8.17 (d, 3H), 8.32-8.33 (d, 1H), 10.80 (s, 1H).

Example 9(2R)-2-(2-Amino-2-methylpropanoylamino)-N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]hexanamideBistrifluoroacetic Acid

This compound was obtained from(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]hexanamideas an off white solid in 92% yield. MS (FD+) m/z 468.2 (M⁺). Anal.calcd. for C₂₅H₃₆N₆O₃.2C₂HF₃O₂: C, 50 .00; H, 5 .50; N, 12.06. Found: C,49.79; H, 5.55; N, 12.07. ¹H nmr (DMSO-d₆): δ0.84-0.88 (m, 3H),1.28-1.30 (m, 4H), 1.50-1.52 (d, 6H), 1.71-1.78 (m, 6H), 2.87-2.89 (m,1H), 3.39-3.40 (m, 2H), 3.67-3.69 (m, 1H), 4.37-4.40 (m, 1H), 6.62 (s,1H), 7.38 (s, 1H), 7.42-7.49 (m, 5H), 8.09-8.13 (d, 1H), 8.20-8.21 (m,3H), 8.37-8.38 (d, 1H), 10.98 (s, 1H), 11.69 (s, broad, 1H).

Example 10N-((1R)-1-{N-[1-(2-Oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}-2-(3-thienyl)ethyl)-2-amino-2-methylpropanamideBistrifluoroacetic Acid

This compound was obtained fromN-((1R)-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}-2-(3-thienyl)ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamideas an off white solid in 90% yield. MS (FD+) m/z 508.2 (M⁺). Anal.calcd. for C₂₆H₃₂N₆O₃S.2C₂HF₃O₂: C, 48.91; H, 4.65; N, 10.9911.41.Found: C, 48.68; H, 4.53; N, 11.26. ¹H nmr (DMSO-d₆): δ1.40 (s, 3H),1.50-1.52 (d, 3H), 1.72-1.85 (m, 4H), 2.92-2.93 (m, 1H), 3.22 (m, 1H),3.32 (m, 1H), 3.39-3.42 (m, 2H), 3.67-3.69 (m, 1H), 4.70-4.74 (m, 1H),6.59 (s, 1H), 6.93-6.98 (d, 2H), 7.32-7.33 (d, 1H), 7.39-7.49 (m, 6H),7.92-7.96 (d, 1H), 8.15-8.16 (d, 3H), 8.57-8.58 (d, 1H), 8.70 (s, broad,1H), 10.99 (s, 1H).

Example 11N-[(1R)-1-(N-{1-[2-(4-Methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)-2-(3-thienyl)ethyl]2-amino-2-methylpropanamideBistrifluoroacetic Acid

This compound was obtained fromN-[(1R)-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)-2-(3-thienyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamideas an off white solid in 84% yield. MS (FD+) m/z 536.2 (M⁺). Anal.calcd. for C₂₈H₃₆N₆O₃S.2C₂HF₃O₂: C, 50.26; H, 5.01; N, 10.99. Found: C,50.06; H, 4.89; N, 11.00. ¹H nmr (DMSO-d₆): δ0.73-0.74 (d, 2H),0.89-0.90 (d, 2H), 0.95-1.20 (m, 1H), 1.28-1.52 (m, 8H), 1.60-1.63 (m,1H), 2.64-2.69 (m, 1.5H), 3.03 (t, 0.5H), 3.19-3.22 (t, 1H), 3.30-3.34(t, 1H), 3.71-3.75 (m, 1H), 4.40-4.44 (m, 1H), 4.71 (m, 1H), 6.85-6.98(m, 3H), 7.32-7.48 (m, 7H), 7.92-7.97 (m, 1H), 8.16-8.17 (d, 3H),8.57-8.58 (d, 1H), 11.02 (s, 1H), 11.3 (s, broad, 1H).

Example 12N-((1R)-2-Benzo[b]thiophen-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl)ethyl)-2-amino-2-methylpropanamideBistrifluoroacetic Acid

This compound was obtained fromN-((1R)-2-benzo[b]thiophen-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide as an off white solid in 89% yield. MS (FD+) m/z 557.9 (M⁺).¹H nmr (DMSO-d₆): δ1.21-1.22 (d, 2H), 1.28-1.29 (d, 1H), 1.46-1.49 (m,3H), 1.75-1.87 (m, 4H), 2.93-2.95 (m, 1H), 3.36-3.42 (m, 3.5H),3.68-3.69 (m, 1.5H), 4.95-4.98 (m, 1H), 6.57 (s, 1H), 7.39-7.54 (m, 9H),7.79-8.05 (m, 6H), 8.15 (m, 0.5H), 8.30 (m, 0.5H), 8.55-8.56 (m, 1H),10.95-11.05 (d, 1H).

Example 13 N-[(1R)-2-Benzo[b]thiophen-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)ethyl]-2-amino-2-methylpropanamideBistrifluoroacetic Acid

This compound was obtained fromN-[(1R)-2-benzo[b]thiophen-3-yl-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamideas an off white solid in 72% yield. MS (FIA) m/z 586.7 [(M+H)⁺]. ¹H nmr(DMSO-d₆): δ0.74-0.76 (d, 2H), 0.89-0.90 (d, 2H), 1.0-1.64 (m, 10H),2.65-2.70 (m, 1.5H), 3.04 (t, 0.5H), 3.15-3.35 (m, 1.5H), 3.62-3.75 (m,1H), 4.42-4.45 (m, 1H), 4.97 (m, 1H), 6.84-6.89 (d, 1H), 7.39-7.57 (m,1OH), 7.79-8.20 (m, 6H), 8.36 (t, 0.5H), 8.53-8.57 (m, 1H), 10.97-11.06(d, 1H).

Example 14N-[(1R)-1-(N-{1-[(N,N-Dimethylcarbamoyl)-2-naphthylmethyl}imidazol-4-yl}carbamoyl)-2-indol-3-ylethyl]-2-amino-2-methylpropanamideDihydrochloride

This compound was obtained from the reaction of2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)aceticacid and dimethylamine followed by deprotection according to the generalprocedure as an off white solid in 90% yield. MS (FIA) m/z 566.6[(M+H)⁺]. ¹H nmr (DMSO-d₆): δ1.36-1.37 (d, 3H), 1.51-1.53 (d, 3H), 2.92(s, 3H), 2.99 (s, 3H), 3.19-3.22 (m, 1H), 3.27-3.31 (m, 1H), 4.68-4.73(m, 1H), 6.90-6.94 (m, 1H), 6.97-7.03 (m, 1H), 7.29-7.33 (m, 2H), 7.38(s, 1H), 7.55 (s, 1H), 7.60-7.62 (t, 3H), 7.73 (t, 1H), 7.98-8.06 (m,4H), 8.36-8.37 (d, 3H), 8.72-8.74 (d, 2H), 10.97 (s, 1H), 11.49 (s, 1H).

Example 15N-((1R)-2-(2-Naphthyl)-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-amino-2-methylpropanamide

This compound was obtained from2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-(2-naphthyl)propanoylamino)imidazolyl]-2-phenylaceticacid and pyrrolidine followed by deprotection according to the generalprocedure to give a tan foam in 53% yield. MS (FD⁺) m/z 552 (M⁺). ¹H nmr(CDCl₃): δ1.06-1.25 (m, 9H), 1.81-1.92 (m, 3H), 3.12-3.13 (m, 1H),3.44-3.61 (m, 4H), 5.03-5.05 (m, 1H), 5.88 (s, 1H), 7.26-7.44 (m, 13H),7.6 (m, 0.5H), 7.75-7.76 (m, 1H), 8.15 (m, 0.5H), 8.24 (m, 1H), 10.5 (m,1H).

Example 16 Methyl1-(2-{4-[(2R)-2-(2-Amino-2-methylpropanoylamino)-3-(2-naphthyl)propanoylamino]imidazolyl}-2-phenylacetyl)(2S)pyrrolidine-2-carboxylateBistrifluoroacetic Acid

This compound was obtained from2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-(2-naphthyl)propanoylamino)imidazolyl]-2-phenylaceticacid and L-proline methyl ester followed by deprotection according tothe general procedure to give a white solid in 76% yield. MS (FD⁺) m/z610.0 (M⁺). IR (KBr): 1744.15, 1669.60, 1535.15, 1437.31, 1201.83,1136.77, 721.83.

EXAMPLES PART 8 Preparation 1 2-(4-Nitroimidazolyl)-2-phenylacetic acid

Lithium hydroxide (18.1 g, 750 mm, 2 eq) was added to a stirred slurryof ethyl 2-(4-nitroimidazoyl)-2-phenylacetate (Preparation 11 fromExamples Part 1) (104 g, 379 mm) in 250 mL of ethanol. Deionized waterwas added to the resulting mixture and the stirring was continued for 4hours. The ethanol was removed under vacuum and the resulting aqueoussolution was washed with 100 mL of diethyl ether. The aqueous layer wasdiluted with 100 mL of deionized water and the pH was adjusted to 1.8with concentrated HCl after cooling to 12° C. The resulting slurry wasstirred for 30 minutes at less than 5 degrees and filtered. The wet cakewas washed with 100 mL of deionized water and dried under a stream ofair on the filter overnight to yield 90.34 g (96%) of a brown solid. Theproduct may be recrystallized from isopropyl alcohol to give 72.31 g(80% recovery, 77% overall yield) of a tan solid. Elemental analysis:Calculated: %C, 53.45; %H, 3.67; %N, 16.97; Found: %C, 53.67; %H, 3.79;%N, 16.65. MS: 247 (M⁺): IR (cm⁻¹)1719; H¹ nmr (d⁶ DMSO): d 6.51 (s,1H), 7.43-7.55 (m,5H), 7.95 (s,1H), 8.40 (s, 1H)

Preparation 21-(4-Methylpiperidinyl)-2-(4-nitroimidazolyl)-2-phenylethan-1-one

N-Methyl morpholine (2.22 ml, 1.0 eq) was added to a stirred solution of2-(4-nitroimidazolyl)-2-phenylacetic acid (1) (5.0 g, 20.2 mm) and2-chloro-4,6-dimethoxy-1,3,5-triazine (3.61 g, 20.2 mm, 1.0 eq) in 50 mlof anhydrous tetrahydrofuran at 25° C. After stirring the reactionmixture at ambient temperature for 1 h, 4-methylpiperidine (2.39 mL,24.14 mm, 1.1 eq) was added and stirring continued for 50 min. Thereaction mixture was quenched by the addition of 1M HCl. The layers wereseparated and the organic layer was washed with saturated NaHCO3. Theresulting emulsion was broken and all the solids dissolved by theaddition of deionized water. The layers were separated and the organiclayer washed with brine, dried over MgSO4 and filtered. The volatileswere removed under vacuum to give a tan foam (6.08 g, 91% yield). Thefoam was slurried in hexane overnight to achieve partial crystallizationof the product. This was filtered to give a cream colored solid (1.29g,19%) which assayed 97% by HPLC. Analytical data are under PX026948. Thegummy residue was treated with refluxing methyl t-butyl ether tofacilitate crystallization. After refluxing, the slurry was cooled andfiltered to give a cream colored product (3.02 g, 45%). Elementalanalysis: Calculated: %C, 62.18; %H, 6.14; %N, 17.06; Found: %C, 62.05;%H, 3.79; %N, 16.65; MS: 328 (M⁺) IR (cm⁻¹)1659; H¹ nmr: d (d⁶ DMSO):0.5(m,0.4H), 0.70 (d, J+6 Hz, 1.5 H), 0.87 (d, J=6 Hz, 1.5 H), 0.75-1.65(m, 4.6H), 2.50-2.70 (m, 2.5H), 2.9-3.1 (m, 0.5H), 3.5-3.7 (m, 1H),4.28-4.45 (m, 1H), 6.89 (s, 0.5H), 6.94 (s, 0.5H), 7.4-7.5 (m, 5H), 7.79(s, 1H), 8.18 (s, 1H)

Preparation 3 2-(4-Nitroimidazolyl)-2-phenyl-1-pyrrolidinylethane-1-one

N-Methyl morpholine (22.25 ml, 2 eq) was added to a stirred solution of2-(4-nitroimidazolyl)-2-phenylacetic acid (1) (25.03 g, 101.2 mm) and2-chloro-4,6-dimethoxy-1,3,5-triazine (18.1 g, 101.2 mm, 1.0 eq) in 50ml of anhydrous tetrahydrofuran at 25° C. After stirring the reactionmixture at ambient temperature for 1 h, 7.2 mL (101.2 mm, 1.0 eq) ofpyrrolidine was added dropwise. The reaction was stirred at roomtemperature for 2 hours. The reaction mixture was quenched by theaddition of 200 mL of ethyl acetate and 200 mL of 1M HCl. The layerswere separated and the organic layer was washed with 100 mL of saturatedsodium bicarbonate solution. The mixture resulting from the bicarbonatewash was diluted 1:1 with deionized water to dissolve the resultingsolids and the layers were separated. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and the volatiles wereremoved under vacuum to give a brown foam. This foam was dissolved inmethanol, diethyl ether and methylene chloride. Evaporation of thesolvents overnight yielded a brown solid which was slurried in 200 mL ofdiethyl ether for 4 hours. The resulting slurry was filtered and thecake was washed with diethyl ether. The solids were dried under vacuumovernight to give a cream colored product (21.68 g, 71%) d(d⁶DMSO):1.69-1.84 (m, 3H), 2.80-2.85 (m, 0.7H), 3.32-3.41 (m, 3.6H),3.64-3.67 (m, 0.7H), 6.65 (s, 1H), 7.42-7.50 (m, 5H), 7.83 (s, 1H), 8.22(s, 1H)

Preparation 4 Methyl(2S)-1-[2-(4-nitroimidazolyl)-2-phenylacetyl]pyrrolidine-2-carboxylate

N-Methyl morpholine (17.79 ml, 2 eq) was added to a stirred solution of2-(4-nitroimidazolyl)-2-phenylacetic acid (1) (20 g, 80.9 mm) and2-chloro-4,6-dimethoxy-1,3,5-triazine (14.45 g,80.1 mm, 1.0 eq) in 175ml of anhydrous tetrahydrofuran at 25° C. After stirring the reactionmixture at ambient temperature for 1.5 h, 14.45g (80.9 mm, 1.0 eq) ofproline methyl ester hydrochloride was added. The reaction was stirredovernight at room temperature and the solvent was evaporated under astream of nitrogen. The residue was partitioned between 200 Ml of 1M HCland 200 mL of deionized water. The layers were separated and the organiclayer was washed with saturated sodium bicarbonate solution. A quantityof water sufficient to dissolve the resulting solids was added. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered and the volatiles were removed under vacuum to give a brownfoam. The foam was dissolved in methyl t-butyl ether, methylene chlorideand methanol to effect crystallization. The resulting slurry wasfiltered and dried under vacuum to give 17.45 g (60%) of a cream coloredproduct MS: 358 (M⁺) IR (cm⁻¹): 1744, 1668; H¹ nmr d (d⁶ DMSO):1.42-1.46 (m, 3H), 1.6-1.9 (m, 1H), 2.42-2.63 (m,1H), 3.21 (s, 1.5H),3.25 (s, 1.5H), 3.30-3.36 (m, 1H), 4.01-4.06 (m, 1H), 6.36 (s, 0.5H),6.43 (s, 0.5h), 7.0-7.2 (m, 5H), 7.38 (s, 0.5H), 7.41 (s, 0.5H), 7.75(s, 0.5H), 7.83 (s, 0.5H)

Preparation 5 Methyl(2S)-1-[2-(4-aminoimidazolyl)-2-phenylacetyl]pyrrolidine-2-carboxylate,dihydrochloride

Ethanol (12 mL) was added to a mixture of methyl(2S)-1-[2-(4-nitroimidazolyl)-2-phenylacetyl]pyrrolidine-2-carboxylate(4) (148 mg,0.4 mm) and 10% Pd on carbon (15 mg) in a Bradleyhydrogenation apparatus. The stirred reaction mixture was subjected to a60 psi H₂ atmosphere and warmed to 60° C. After 2 hours, the reactionmixture was cooled to room temperature and the catalyst was removed byfiltration. Anhydrous HCl gas was added to the filtered solution untilsaturation. The volatiles were then removed under vacuum to give 0.15 g(100%) of a yellow solid mixed with a brown gum.

Preparation 6 2-(4-aminoimidazolyl)-2-phenyl-1-pyrrolidinylethan-1-one,dihydrochloride

Ethanol (200 mL) was added to a mixture of2-(4-nitroimidazolyl)-2-phenyl-1-pyrrolidinylethan-1-one (3) (0.752 g,2.8 mm) and 10% Pd on carbon (75 mg) in a Bradley hydrogenationapparatus. The stirred reaction mixture was subjected to a 60 psi H₂atmosphere and warmed to 60° C. After 2 hours, the reaction mixture wascooled to room temperature and the catalyst was removed by filtration.Anhydrous HCl gas was added to the filtered solution until saturation.The volatiles were then removed under vacuum to give a light yellowfoam. Diethyl ether and methylene chloride (25:1) were added to the foamand the resulting mixture was stirred overnight to achievecrystallization. The resulting slurry was filtered and the cake waswashed with diethyl ether. The cake was dried under vacuum to give 0.659g (93%) of a yellow solid. LGD 208.

Preparation 72-(4-aminoimidazolyl)-1-(4-methylpiperidinyl)-2-phenylethan-1-one,dihydrochloride

Methanol (140 mL) was added to a mixture of1-(4-methylpiperidyl)-2-(4-nitroimidazolyl)-2-phenylethan-1-one (2)(2.16 g, 6.5 mm) and 0.214 g of 10% palladium on carbon in a Bradleyhydrogenation apparatus. The stirred reaction mixture was subjected to a60 psi H₂ atmosphere and warmed to 60° C. After 2 hours, the reactionmixture was cooled to room temperature and the catalyst was removed byfiltration. Anhydrous HCl gas was added to the filtered solution untilsaturation. The volatiles were then removed under vacuum and the residuewas crystallized from methylene chloride: methyl t-butyl ether 1:3. Theresulting slurry was filtered and the wet cake was washed with methylt-butyl ether and dried under vacuum to give 2.23 (93%)g of a yellowsolid. MS: 298 (M+1⁺); IR (cm⁻¹):1648; H¹ nmr d (d⁶ DMSO):0.11-0.21(m,0.5H), 0.725 (d, J=4.9 Hz, 1.5H), 1.11-1.21 (m, 0.5H), 1.25-1.40 (m,1H), 1.59-1.80 (m, 2H), 2.72-2.81 (m, 1H)3.08-3.15 (m, 0.5H) 3.32 (s,0.5H), 3.32 (s, 0.5H). 3.32 (s. 0.5H) 3.75 (d. J=8 Hz, 1H), 4.50-4.57(dd. J=7.3 Hz, 1H). 4.95 (s, 1H), 6.8 (s, 0.5H), 6.9 (s, 0.5H),7.39-7.60 (m, 5H), 8.29 (s, 0.5H), 8.45 (s, 0.5H)

Example 1N-((1R)-2-indol-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

N-Methyl morpholine (0.28 mL, 8.32 mm, 1 eq) was added to a stirredslurry of 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.46 g, 2.57 mm, 1 eq)and(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoicacid (1 g, 2.57 mm) in 10 mL of anhydrous tetrahydrofuran cooled to lessthan 0° C. After 1.5 hours,2-(4-aminoimidazolyl)-2-phenyl-1-pyrrolidinylethan-1-one, hydrochloride(0.97 g, 2.82 mm, 1.1 eq) was added and stirring was continued at icebath temperatures. The reaction was stirred for 4 hours and quenched bythe addition of 15 mL of deionized water and ethyl acetate. The ethylacetate layer was washed with a saturated sodium bicarbonate solution,dried over magnesium sulfate and the volatiles were removed under vacuumto give the crude product as a light purple foam (1.4 g, 84%) The crudeproduct was purified by preparative chromatography to provide 0.52 g(31.5%) of the product as a foam. ¹H nmr (CDCl₃): δ1.10-1.40 (m, 15H),1.67-1.92 (m, 3H), 2.92-3.60 (m, % H), 4.90 (s, broad, 1H), 5.33 (s,broad, 1H), 5.85 (d, 1H), 6.80-7.05 (m, 3H), 7.13-7.39 (m, 10H),7.44-7.80 (m, 2H), 8.96 (s, broad, 1H), 10.20 (s, broad, 1H).

Example 2N-((1R)-2-indol-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-amino-2-methylpropanamide,2,2,2-trifluoroacetic acid, 2,2,2-trifluoroacetic acid salt

Trifluoroacetic acid (0.57 mL, 7.4 mm, 33 eq) was added to a stirredsolution ofN-((1R)-2-indol-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide(8) (0.152 g, 0.22 mm) in 5 mL of methylene chloride. After stirring atroom temperature for 3 hours, the reaction mixture was diluted with 50mL of diethyl ether. The resulting solids were isolated bycentrifugation and washed with diethyl ether. The solids were driedunder vacuum to give the product as a cream colored solid (0.084 g, 48%)MS (FD+) m/z 541 (M⁺)Anal. calcd. for C₃₀H₃₅N₇O₃.2C₂HF₃O₂: C, 53.06; H,4.85; N, 12.74. Found: C, 52.93; H, 4.88; N, 12.55. ¹H nmr (DMSO-d₆):δ1.29 (s, 3H), 1.46-1.48 (d, 3H), 1.72-1.88 (m, 4H), 2.94 (m, 1H),3.06-3.07 (m, 1H), 3.19-3.20 (m, 1H), 3.40-3.41 (d, 2H), 3.67-3.69 (m,1H), 4.78 (s, broad, 1H), 6.53 (s, 1H), 6.93-6.97 (m, 1H), 7.06 (m, 1H),7.20 (d, 1H), 7.31-7.36 (m, 2H), 7.42-7.42 (m, 4H), 7.73-7.80 (m, 2H),8.01 (s, broad, 2H), 8.36-8.38 (d, 1H), 10.82-10.85 (d, 2H).

Example 3 Methyl1-{2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-phenylacetyl}pyrrolidine-2-carboxylate

NMR data support the assigned structure. MS: 699.9

Example 4 Methyl1-(2-{4-[(2R)-2-(2-amino-2-methylpropanoylamino)-3-indol-3-ylpropanoylamino]imidazolyl}-2-phenylacetyl)pyrrolidine-2-carboxylate,dihydrochloride

NMR data support the assigned structure. MS: 599

Example 5N-((1R)-2-(2-naphthyl)-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

NMR data support the assigned structure. MS: 652

Example 6N-((1R)-2-(2-naphthyl)-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-amino-2-methylpropanamide,dihydrochloride

NMR data support the assigned structure. MS: 552

Example 7N-[(1R)-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)-2-(2-naphthyl)ethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

NMR data support the assigned structure. MS: 680

Example 8N-[(1R)-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)-2-(2-naphthyl)ethyl]-2-amino-2-methylpropanamidedihydrochloride

NMR data support the assigned structure. MS: 581 (M+1⁺)

Example 9N-((1R)-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}-2-phenylethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

NMR data support the assigned structure. MS: 602

Example 10N-((1R)-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}-2-phenylethyl)-2-amino-2-methylpropanamide,dihydrochloride

NMR data support the assigned structure. MS: 502

Example 11N-[(1R)-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)-2-phenylethyl]-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

NMR data support the assigned structure. MS: 630

Example 12N-[(1R)-1-(N-{1-[2-(4-methylpiperidyl)-2-oxo-1-phenylethyl]imidazol-4-yl}carbamoyl)-2-phenylethyl]-2-amino-2-methylpropanamide,dihydrochloride

NMR data support the assigned structure. MS: 530

Example 13(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]-4-phenylbutanamide

NMR data support the assigned structure. MS: 616

Example 14(2R)-2-(2-amino-2-methylpropanoylamino)-N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]-4-phenylbutanamide,dihydrochloride

NMR data support the assigned structure. MS: 517 (m+1⁺)

Example 15(2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-N-{1-[2-(4-methylpiperidinyl)-2-oxo-1-phenylethyl]imidazol-4-yl}-4-phenylbutanamide

NMR data support the assigned structure.

Example 16(2R)-2-(2-amino-2-methylpropanoylamino)-N-{1-[2-(4-methylpiperidinyl)-2-oxo-1-phenylethyl]imidazol-4-yl}-4-phenylbutanamide,dihydrochloride

NMR data support the assigned structure. MS: 544

Example 17 Methyl1-{2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-4-phenylbutanoylamino)imidazolyl]-2-phenylacetyl)pyrrolidine-2-carboxylate

NMR data support the assigned structure.

Example 18 Methyl1-(2-{4-[(2R)-2-(2-amino-2-methylpropanoylamino)-4-phenylbutanoylamino]imidazolyl}-2-phenylacetyl)pyrrolidine-2-carboxylate,dihydrochloride

NMR data support the assigned structure. MS:575 (m+1⁺)

EXAMPLES PART 9 Example 1 Pituitary Cell Culture Assay for GrowthHormone Secretion

Thirty-two 250 g male Sprague-Dawley rats were used for each assay. Theanimals were killed by decapitation and anterior pituitaries wereremoved and placed into ice cold culture medium. The pituitaries weresectioned into eighths and enzymatically digested using trypsin (SigmaChemical) to weaken connective tissue. Pituitary cells were dispersed bymechanical agitation, collected, pooled and then seeded into 24-wellplates (300,000 cells/well). After 4 days of culture, the cells formedan even monolayer. Cells were then washed with medium and challenged tosecrete GH by the addition of GH secretagogues to the medium. After 15min at 37° C., the medium was removed and stored frozen untilradioimmunoassays for rat GH were performed. Doses of secretagogue wereadded in quadruplicate. Representative Data is provided in Table 1below. Compounds disclosed herein are active in the assay as described.Both EC₅₀ and efficacy values were calculated by the 4-parameterlogistic equation. Such values were pooled and represented as mean +/−standard error, when appropriate.

TABLE 1 EXAMPLES GH PART 1 secretion Example # EC₅₀ (mM) 6 5.53 8 2.39

EXAMPLES PART 10 Example 1 Initial Efficacy

In vivo growth hormone secretion and growth hormone selectivity(corticosterone levels) screening were assessed in immature rats,initially with parenteral dosing, followed later by oral dosing withselected compounds. In vivo growth hormone secretagogue activity isexamined in immature rats (approx. 75 g body weight) by parenteral(s.c.) administration initially. Compounds displaying potent in vitroactivity (≦approx. 0.5 mM) are tested in vivo. Compounds displayinggrowth hormone secretory activity at ≦30 mg/kg s.c. are further testedfor growth hormone selectivity by examining effects on serumcorticosterone in immature rats. Growth stimulating efficacy has beendemonstrated for GHRP-2 (parenteral administration) in such an in vivoassay.

Example 2 Effects of Growth Hormone Secretagogues in the Rat Model ofCongestive Heart Failure

The effects of growth hormone and a GHRP (GRP-2) on the progression ofheart failure were examined in a rat genetic model of heart failure, theSHHF/Mcc-fa ^(cp) rat (McCune et al., Mechanisms of Heart Failure,Singal, et al., eds., Kluwer Academic Publishers, 1995). This modelrepresents a well-established small animal model of heart failure thatmimics the important aspects of dilated cardiomyopathy, the setting inwhich dramatic effects of growth hormone have been observed clinically(Fazio et al., New England Journal of Medicine, 334: 809-14, 1996).

Rats were dosed with 0.05 to 0.01 mg/kg of GRP-2 per day, or with 0.1 to1.0 mg/kg of growth hormone per day. The effects of growth hormone andGHRP-2 were compared to those of a positive control drug in this model,Captopril®, during a 2 month course of therapy, starting during theearly stages of heart failure (14-16 months of age). Hemodynamic as wellas biochemical indices of heart failure together with growth hormone,levels of IGF-1, insulin, and atrial natriuretic peptide (ANP), andoverall survival were monitored.

The data presented in Table 2, below, indicates an increased survivalrate in rats treated with GRP-2 over those treated with growth hormone.Importantly, none of the animals treated with GRP-2 died of heartfailure.

TABLE 2 Survival Analysis Group Survival Cause of Death/SacrificeControl 3/5 CHF (2) GH low 2/5 CHF(1), CHF(1), leuk(1) GH high 2/5CHF(1), CHF + PT(1), CHF(1) GRP-2 low 4/5 leuk(1) GRP-2 high 4/5 PT(1)PT = pituitary tumor leuk = leukemia

Data presented in FIGS. 1-8 provide further evidence of theeffectiveness of growth hormone secretagogue therapy in the rat model ofCHF. Specifically, FIG. 1 shows an increase in heart and lung weight inanimals treated with growth hormone, as opposed to a trend towarddecreased weights in those animals treated with GRP-2.

FIGS. 2-4 show an increase in the levels of corticosterone levels inthose test animals treated with growth hormone, as opposed to thoseanimals treated with GRP-2. Increased levels of corticosterone wereobserved in rats treated with growth hormone, which was seen as afunction of heart failure progression.

FIGS. 5-7 show an increase in atrial natriuretic peptide (ANP) inanimals treated with growth hormone, as opposed to a dose-dependenttrend toward decreased ANP in those treated with GRP-2. Levels of atrialnatriuretic peptide (ANP) are known to increase in heart failure.

FIG. 8 shows the end systolic volume in rats treated with growth hormoneor GRP-2, which indicates a decrease in ventricular systolic function inrats treated with growth hormone, as opposed to rats treated with GRP-2.

Overall, these results indicating a decrease in the incidence of heartfailure in rats treated with GRP-2 versus those treated with growthhormone are surprising and unexpected.

Example 3 Effect of Growth Hormone Secretagogues in the Canine Model ofCongestive Heart Failure

Dog models appear to closely mimic human heart failure from thestandpoint of response to drug therapy (Sabbah et al., Circulation 89:2852-9, 1994; Tsutsui et al., J. Clin. Invest. 93: 2639-2648, 1994; andWang et al., Amer. J. Physiol. 266: H670-80, 1994).

The effect of the administration of a growth hormone secretagogue may beexamined in a canine model of congestive heart failure as follows. Aftertable training for several weeks, the subject dogs are anesthetized andby means of a left thorocotomy, pacing wires are placed on the leftatrial appendage and right ventricle, tygon catheters are inserted intothe descending aorta and the right and left atria, a solid statemicromanometer is inserted into the left ventricle, a flow probe isplaced around the ascending aorta and the coronary artery, andpiezoelectric crystals are placed in the left ventricle. If desired,renal and iliac arterial flow tubes may also be placed. The animals arepermitted to recover for 14 days during which time basal measurementsare obtained. Pacing of the right ventricle at approximately 240beats/minute is initiated on day 14 after surgery. As demonstrated byhemodynamic data at baseline and at three weeks after pacing in aconscious dog, this model not only achieves significant left ventriculardysfunction (for example, a decrease in left ventricular change inpressure over change in time and ejection fraction, increase in leftventricular end diastolic pressure and heart rate), but alsodemonstrates many of the signs of congestive heart failure seen in theclinic, including exercise intolerance, pulmonary edema, and ascites.

On day 14 after surgery, the subject animals are randomized (targetingfive animals in each group). A compound of formula I, or GRP-2, orvehicle is administered beginning at the time of the initiation ofpacing throughout duration of the study. Cardiac function, peripheralhemodynamics, exercise performance, and body weights are measured in thebaseline study and weekly after initiation of pacing (three weekstotal). Twenty-one days after initiation of pacing, the animals aresacrificed and the relative effect of administration of the growthhormone secretagogue on ventricular modeling, left ventricular mass, andbody weight is determined.

We claim:
 1. A method of modulating cardiac function which comprisesadministering to a patient in need thereof an effective amount of GRP-2.2. A method of modulating cardiac function which comprises administeringto a patient in need thereof an effective amount of a compound offormula I

wherein: A is C₁-C₆alkyl, aryl, C₁-C₆alkylaryl,C₁-C₆alkyl(O)C₁-C₆alkylaryl, C₁-C₆alkyl(S)C₁ 14 C₆alkylaryl, indolyl,indolinyl, thienyl, (C₁-C₆alkyl)thienyl, benzothienyl, benzofuranyl,naphthanyl, cyclohexyl, (C₁-C₆alkyl)indolyl, (C₁-C₆alkyl)benzothienyl,(C₁-C₆alkyl)naphthanyl, (C₁-C₆alkyl)benzofuranyl, and(C₁-C₆alkyl)cyclohexyl; B is NH₂, NHR₁, C₁-C₆alkylNH₂, C₁-C₆alkylNHR₁,C₁-C₆alkylarylNH₂, C₁-C₆alkylarylNHR₁, C₁-C₆alkylcyclohexylNH₂,C₁-C₆alkylcyclohexylNHR₁, R₁-piperidin-3-yl(C₁-C₆alkyl),R₁-piperidin-2-yl(C₁-C₆alkyl), R₁-piperidin-4-yl(C₁-C₆alkyl),R₁-quinolin-2-yl(C₁-C₆alkyl), R₁-(2,4-dihydroquinolin-2-yl(C₁-C₆alkyl),R₁-isoquinolin-2-yl(C₁-C₆alkyl), andR₁-(2,4-dihydroisoquinolin-2-yl(C₁-C₆alkyl); R₁ is hydrogen, C₁-C₆alkyl,C₁-C₆alkyl(OH), or C₁-C₆alkylenyl(OH)R₂; R₂ is C₁-C₆alkyl, C₁-C₆alkenyl,C₁-C₆alkyl(O)C₁-C₆ alkyl, C(O)O—C₁-C₆ alkyl, aryl, or C₁-C₆alkylaryl; Xis C₁-C₆alkylenyl, O, S, NH, or N(C₁-C₆alkyl); V is selected from thegroup consisting of

W is S, O, NH, or CH₂; Y is N or CH; Z is N or CH; Y′ is N or CH; Z′ isN or CH; R₄ and R₅ are independently hydrogen, C₁-C₆alkyl, aryl,C₁-C₆alkylaryl, C(O)O(C₁-C₆alkyl), C(O)N(C₁-C₆alkyl)₂, orC₁-C₆alkylCOR₇; R₇ is hydrogen, C₁-C₆alkyl, pyrrolidinyl, piperidinyl,homoproline, or proline; D is hydrogen, C₁-C₆alkyl,C₁-C₆alkyl(O)(CO)C₁-C₆alkyl, C₁-C₆alkyl(O)(CO)N(C₁-C₆alkyl)₂,C₁-C₆alkylaryl, C(O)R₆, C₁-C₆alkyl(O)R₆, C₁-C₆alkyl(OH),C₁-C₆alkylC(O)R₆, C₁-C₆alkylR₆aryl, (C₁-C₆alkyl)NHSO₂(C₁-C₆alkyl),(C₁-C₆alkyl)NHSO₂(aryl); R₆ is H, C₁-C₆alkyl, aryl, naphthyl,C₁-C₆alkylaryl, acetyl, NH₂, NH(C₁-C₆alkyl),NH(C₁-C₆alkyl)O(C₁-C₆alkyl), NH(C₁-C₆alkyl)S(C₁-C₆alkyl),NH(C₁-C₆alkylidenyl)OCH₃, NH(C₁-C₆alkyl)aryl, NH(C₃-C₆ cycloalkyl),NH(C₁-C₆alkyl)C(O)(C₁-C₆alkyl), NH(C₁-C₆alkyl)NH(C₁-C₆alkyl),NH(C₁-C₆alkyl)NH(C₁-C₆alkylaryl), NHSO₂(C₁-C₆alkylaryl),NH(C₁-C₆alkyl)C(O)O(C₁-C₆alkyl), NH(naphthyl), N(C₁-C₆alkyl)₂,N(C₁-C₆alkyl)(aryl), N(C₁-C₆alkyl)(C₁-C₆alkylaryl), O(C₁-C₆alkyl),O(aryl), O(C₁-C₆alkylaryl), piperidinyl, piperidinyl-C(O)NH(C₁-C₆alkyl),piperidinyl-C(O)NH(C₁-C₆alkylaryl), piperidinyl-C(O)N(C₁-C₆alkyl)₂,piperidinyl-C(O)N(C₁-C₆alkyl)(aryl), pyrrolidinyl, pyrrolidinylC(O)NH(aryl), pyrrolidinyl C(O)NH(C₁-C₆alkyl), pyrrolidinylC(O)N(C₁-C₆alkyl)₂, pyrrolidinyl C(O)NH(C₁-C₆alkylaryl), pyrrolidinylC(O)NH(C₁-C₆alkyl)(aryl), pyrrolinyl, morpholino, hexamethyleneimino,heptamethyleneimino, quinolinyl, 2,4-dihydroquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,4-dihydroisoquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, indolinyl, an amino acid selected fromthe group consisting of proline, homoproline, glycine, alanine, valine,leucine, isoleucine, tyrosine, tryptophan, phenylalanine, serine,threonine, asparagine, glutamic acid, aspartic acid, lysine, arginine,glutamine, histidine, cysteine, and methionine, or a nitrogen-containingheterocycle selected from the group consisting of

E is hydrogen, C₁-C₆alkyl, C(O)C₁-C₆alkyl, aryl, (aryl)C(O)NR₆,(aryl)(C₁-C₆alkyl)C(O)R₆, C₁-C₆alkylaryl, C(O)aryl, C₁-C₆ alkylC(O)aryl,naphthyl, C₁-C₆alkylnaphthyl, C(O)naphthyl, C₁-C₆alkylC(O)naphthyl,heteroaryl, C₁-C₆alkylheteroaryl, C(O)heteroaryl, C₁-C₆alkylC(O)heteroaryl, indanyl, C₁-C₆alkylindanyl, C(O)indanyl,C₁-C₆alkylC(O)indanyl, cycloalkyl; or D and E combine to form indanyl,fluorenyl, or cycloalkyl; G is hydrogen, C₁-C₆alkyl, aryl,C₁-C₆alkylaryl, and C₁-C₆alkenyl; J is hydrogen, C₁-C₆alkyl, aryl, andC₁-C₆alkylaryl; L is hydrogen, C₁-C₆alkyl, C(O)OC₁-C₆alkyl, aryl,C₁-C₆alkylaryl, C(O)OC₁-C₆alkylaryl, C₁-C₆alkenyl, —F, and —CN,C₁-C₆alkyl-OH, C₁-C₆alkyl-O—C₁-C₆alkyl, C₁-C₆alkyl-C(O)R₆; or apharmaceutically acceptable salt or solvate thereof.
 3. A methodaccording to claim 2 wherein A is selected from the group consisting of


4. A method according to claim 2 wherein B is


5. A method according to claim 3 wherein X is NH.
 6. A method accordingto claim 2 wherein V is selected from the group consisting of


7. A method according to claim 2 wherein D is —C(O)R₆, and R₆ is1-pyrrolidinyl, 1-piperidinyl, 4-methoxy-1-piperidinyl,


8. A method according to claim 2 wherein E is


9. A method according to claim 2 wherein said patient is a human.
 10. Amethod for the treatment or prevention of congestive heart failure whichcomprises administering to a patient in need of said treatment aneffective amount of GRP-2, wherein the GRP-2 increases the levels ofendogenous growth hormone.
 11. A method for the treatment or preventionof congestive heart failure which comprises administering to a patientin need of said treatment an effective amount of a compound of formula I

wherein: A is C₁-C₆alkyl, aryl, C₁-C₆alkylaryl,C₁-C₆alkyl(O)C₁-C₆alkylaryl, C₁-C₆alkyl(S)C₁-C₆alkylaryl, indolyl,indolinyl, thienyl, (C₁-C₆alkyl)thienyl, benzothienyl, benzofuranyl,naphthanyl, cyclohexyl, (C₁-C₆alkyl)indolyl, (C₁-C₆alkyl)benzothienyl,(C₁-C₆alkyl)naphthanyl, (C₁-C₆alkyl)benzofuranyl, and(C₁-C₆alkyl)cyclohexyl; B is NH₂, NHR₁, C₁-C₆alkylNH₂, C₁-C₆alkylNHR₁,C₁-C₆alkylaryl NH₂, C₁-C₆alkylarylNHR₁, C₁-C₆alkylcyclohexylNH₂,C₁-C₆alkylcyclohexylNHR₁, R₁-piperidin-3-yl(C₁-C₆alkyl),R₁-piperidin-2-yl(C₁-C₆alkyl), R₁-piperidin-4-yl(C₁-C₆alkyl),R₁-quinolin-2-yl(C₁-C₆alkyl), R₁-(2,4-dihydroquinolin-2-yl(C₁-C₆alkyl),R₁-isoquinolin-2-yl(C₁-C₆alkyl), andR₁-(2,4-dihydroisoquinolin-2-yl(C₁-C₆alkyl); R₁ is hydrogen, C₁-C₆alkyl,C₁-C₆alkyl(OH), or C₁-C₆alkylidenyl(OH)R₂; R₂ is C₁-C₆alkyl,C₁-C₆alkenyl, C₁-C₆alkyl(O)C₁-C₆ alkyl, C(O)O—C₁-C₆ alkyl, aryl, orC₁-C₆alkylaryl; X is C₁-C₆alkylenyl, O, S, NH, or N(C₁-C₆alkyl); V isselected from the group consisting of

W is S, O, NH, or CH₂; Y is N or CH; Z is N or CH; Y′ is N or CH; Z′ isN or CH; R₄ and R₅ are independently hydrogen, C₁-C₆alkyl, aryl,C₁-C₆alkylaryl, C(O)O(C₁-C₆alkyl), C(O)N(C₁-C₆alkyl)₂, orC₁-C₆alkylCOR₇; R₇ is hydrogen, C₁-C₆alkyl, pyrrolidinyl, piperidinyl,homoproline, or proline; D is hydrogen, C₁-C₆alkyl,C₁-C₆alkyl(O)(CO)C₁-C₆alkyl, C₁-C₆alkyl(O)(CO)N(C₁-C₆alkyl)₂,C₁-C₆alkylaryl, C(O)R₆, C₁-C₆alkyl(O)R₆, C₁-C₆alkyl(OH),C₁-C₆alkylC(O)R₆, C₁-C₆alkylR₆, aryl, (C₁-C₆alkyl)NHSO₂(C₁-C₆alkyl),(C₁-C₆alkyl)NHSO₂(aryl); R₆ is H, C₁-C₆alkyl, aryl, naphthyl,C₁-C₆alkylaryl, acetyl, NH₂, NH(C₁-C₆alkyl),NH(C₁-C₆alkyl)O(C₁-C₆alkyl), NH(C₁-C₆alkyl)S(C₁-C₆alkyl),NH(C₁-C₆alkylidenyl)OCH₃, NH(C₁-C₆alkyl)aryl, NH(C₃-C₆ cycloalkyl),NH(C₁-C₆alkyl)C(O)(C₁-C₆alkyl), NH(C₁-C₆alkyl)NH(C₁-C₆alkyl),NH(C₁-C₆alkyl)NH(C₁-C₆alkylaryl), NHSO₂ (C₁-C₆alkylaryl),NH(C₁-C₆alkyl)C(O)O(C₁-C₆alkyl), NH(naphthyl), N(C₁-C₆alkyl)₂,N(C₁-C₆alkyl)(aryl), N(C₁-C₆alkyl)(C₁-C₆alkylaryl), O(C₁-C₆alkyl),O(aryl), O(C₁-C₆alkylaryl), piperidinyl, piperidinyl-C(O)NH(C₁-C₆alkyl),piperidinyl-C(O)NH(C₁-C₆alkylaryl), piperidinyl-C(O)N(C₁-C₆alkyl)₂,piperidinyl-C(O)N(C₁-C₆alkyl)(aryl), pyrrolidinyl, pyrrolidinylC(O)NH(aryl), pyrrolidinyl C(O)NH(C₁-C₆alkyl), pyrrolidinylC(O)N(C₁-C₆alkyl)₂, pyrrolidinyl C(O)NH(C₁-C₆alkylaryl), pyrrolidinylC(O)NH(C₁-C₆alkyl)(aryl), pyrrolinyl, morpholino, hexamethyleneimino,heptamethyleneimino, quinolinyl, 2,4-dihydroquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,4-dihydroisoquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, indolinyl, an amino acid selected fromthe group consisting of proline, homoproline, glycine, alanine, valine,leucine, isoleucine, tyrosine, tryptophan, phenylalanine, serine,threonine, asparagine, glutamic acid, aspartic acid, lysine, arginine,glutamine, histidine, cysteine, and methionine, or a nitrogen-containingheterocycle selected from the group consisting of

E is hydrogen, C₁-C₆alkyl, C(O)C₁-C₆alkyl, aryl, (aryl)C(O)NR₆,(aryl)(C₁-C₆alkyl)C(O)R₆, C₁-C₆alkylaryl, C(O)aryl, C₁-C₆alkylC(O)aryl,naphthyl, C₁-C₆alkylnaphthyl, C(O)naphthyl, C₁-C₆alkylC(O)naphthyl,heteroaryl, C₁-C₆alkylheteroaryl, C(O)heteroaryl,C₁-C₆alkylC(O)heteroaryl, indanyl, C₁-C₆alkylindanyl, C(O)indanyl,C₁-C₆alkylC(O)indanyl, cycloalkyl; or D and E combine to form indanyl,fluorenyl, or cycloalkyl; G is hydrogen, C₁-C₆alkyl, aryl,C₁-C₆alkylaryl, and C₁-C₆alkenyl; J is hydrogen, C₁-C₆alkyl, aryl, andC₁-C₆alkylaryl; L is hydrogen, C₁-C₆alkyl, C(O)OC₁-C₆alkyl, aryl,C₁-C₆alkylaryl, C(O)OC₁-C₆alkylaryl, C₁-C₆alkenyl, —F, and —CN,C₁-C₆alkyl-OH, C₁-C₆alkyl-O—C₁-C₆alkyl, C₁-C₆alkyl-C(O)R₆; or apharmaceutically acceptable salt or solvate thereof; wherein thecompound of formula I increases the levels of endogenous growth hormone.12. A method according to claim 11 wherein said patient is a human. 13.A method according to claim 2 which further comprises the administrationof an effective amount of an angiotensin converting enzyme (ACE)inhibitor.
 14. A method according to claim 2 which further comprises theadministration of an effective amount of an antihypertensive agent. 15.A method according to claim 2 which further comprises the administrationof an effective amount of a diuretic.
 16. A method according to claim 2which further comprises the administration of an effective amount of aβ-blocker.
 17. A method according to claim 11 which further comprisesthe administration of an effective amount of an angiotensin convertingenzyme (ACE) inhibitor.
 18. A method according to claim 11 which furthercomprises the administration of an effective amount of anantihypertensive agent.
 19. A method according to claim 11 which furthercomprises the administration of an effective amount of a diuretic.
 20. Amethod according to claim 11 which further comprises the administrationof an effective amount of a β-blocker.
 21. A method of diminishing lossof body weight in a mammal following congestive heart failure whichcomprises the administration of a therapeutically effective amount ofGRP-2.
 22. A method of enhancing recovery of a mammal followingcongestive heart failure which comprises the administration of atherapeutically effective amount of GRP-2.
 23. A method for screeningcompounds having growth hormone secretagogue activity for the ability tomodulate cardiac function, which comprises the administration of saidcompounds to a SHHF/Mcc-fa ^(cp) rat, wherein said rat exhibitscongestive heart failure.
 24. A method according to claim 1 wherein saidpatient is a human.
 25. A method according to claim 1 which furthercomprises the administration of an effective amount of an angiotensinconverting enzyme (ACE) inhibitor.
 26. A method according to claim 1which further comprises the administration of an effective amount of anantihypertensive agent.
 27. A method according to claim 1 which furthercomprises the administration of an effective amount of a diuretic.
 28. Amethod according to claim 1 which further comprises the administrationof an effective amount of a β-blocker.
 29. A method according to claim10 which further comprises the administration of an effective amount ofan angiotensin converting enzyme (ACE) inhibitor.
 30. A method accordingto claim 10 which further comprises the administration of an effectiveamount of an antihypertensive agent.
 31. A method according to claim 10which further comprises the administration of an effective amount of adiuretic.
 32. A method according to claim 10 which further comprises theadministration of an effective amount of a β-blocker.
 33. A methodaccording to claim 10 wherein said patient is a human.